Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Metopic frontal suture in a patient with severe dentofacial deformity undergoing bimaxillary surgery.

Six cranial fontanelles are present in newborns along with cranial sutures. Cranial sutures are a synarthrosis type of joints that occur in the skull after closure of fontanelles. Because of ossification up to 24 months, all fontanelles should be closed. Normal frontal bone consists of only frontonasal, frontozygomatic, frontomaxillaris, frontolacrimalis, and main coronal sutures. Metopic frontal suture occurs very rarely in adults. Some metopic frontal sutures might be related to genetic or general disorders or perhaps are related to an improper ossification. In some cases, it persists as a complete suture extending from the nasion to the anterior angle of the bregma, and this condition is called metopism, or metopic suture. In this article, we present a patient with metopic frontal suture diagnosed accidentally during preparation for bimaxillary orthognathic surgery.

Correction of depressed forehead with BoneSource in cleidocranial dysplasia.

Cleidocranial dysplasia is a well-documented rare congenital disorder of the bone characterized by abnormalities of the skull, clavicle, and dentition. Despite numerous observations, there are still comparatively few reports regarding patients with cleidocranial dysplasia that focus on the impact of reconstruction of these defects on facial aesthetics. We report a 19-year-old woman with opened metopic and sagittal sutures and delayed closure of the anterior fontanelle. Through bicoronal incision and pericranial elevation, the defect was fully exposed. BoneSource was used to fill the cranial defect and was contoured to the desired cosmetic outcome. During a 24-month follow-up period, no absorption or recurrence was seen, and the patient was satisfied.

[A neonate without claviculae]. / Een neonaat met verkorte claviculae.

A 1-week-old girl, term born after a non-complicated parturition, presented with abnormal clavicles. At physical examination small and short clavicles were seen, as well as a widened anterior and posterior fontanelle. An X-ray of the thorax showed hypoplastic clavicles and an X-ray of the skull showed delayed ossification of the bones, hypoplasia of the maxilla and extra teeth. This led to the diagnosis 'cleidocranial dysplasia'.

Ichthyosis vulgaris and pycnodysostosis: an unusual occurrence.

Pycnodysostosis is a rare autosomal recessive disorder whose gene responsible for this phenotype (CTSK), mapped to human chromosome 1q21, code for the enzyme cathepsin K, a lysosomal cysteine protease; with an estimated incidence of 1.7 per 1 million births. This clinical entity includes micromelic dwarfism, increased radiological bone density, dysplasia of the skull, acro-osteolysis, straightening of the mandibular angle and in some cases, dysplasia of the acromial end of the clavicle. Oral and maxillo-facial manifestations of this disease are very clear. Herein we reported a case of pycnodysostosis, showing short stature with widening of the sutures, unfused anterior and posterior fontanelles, crowding of teeth with dental caries and typical radiological features associated with ichthyosis vulgaris and palmoplantar keratoderma.