The Rare Association of Cleft Lip and/or Palate and Wilms Tumor.

There is currently no recognized connection between the occurrence of cleft lip and/or palate (CL/P) and Wilms tumor (WT). A retrospective review of cleft team records (2001-2015) revealed 3 cases of children, all male, with concomitant diagnoses of CL/P and WT treated at our institution. These patients presented as infants for care of their CL/P, all with additional congenital anomalies, developmental delays, and growth delays. Between the ages of 1 and 4 years, each was diagnosed with WT, which was treated with chemotherapy and partial nephrectomy, +/- radiation, leading to full remission in all cases.

Family history and clefting as major criteria for CHARGE syndrome.

CHARGE syndrome is an autosomal dominant malformation syndrome associated with mutations in CHD7. The condition is typically sporadic with few familial cases reported. The diagnosis of CHARGE syndrome is based on a combination of major and minor criteria comprised of structural and functional abnormalities, most of which are part of the original CHARGE acronym, although additional anomalies have been added. To date, family history has not been considered in the diagnostic criteria. Here we report a family with a previously unreported missense mutation in exon 31 of CHD7, in which family history played a role in the diagnosis of CHARGE syndrome. Given the tremendous phenotypic variability and the dominant nature of CHARGE syndrome, we propose that family history be included as a major diagnostic criterion. A positive family history would include any individual with an apparently isolated unilateral major CHARGE anomaly or someone with a few of the minor features. Our cases support this proposal; had family history not been considered in this case, CHD7 testing might not have been pursued, leading to incomplete medical follow-up and erroneous genetic counseling. Additionally, with the increased incidence of orofacial clefting in this family, as well as in the literature, we suggest that cleft lip and/or palate be added to the major diagnostic criteria for CHARGE syndrome.

Sleep patterns and problems among children with 22q11 deletion syndrome.

BACKGROUND: To delineate sleep habits and problems in children with 22q11.2 deletion syndrome (22q11DS). METHODS: Thirty children, age 1-15 (mean 6.8) years, participated in the study, which was an internet-based anonymous survey of parents of children with 22q11DS administered via the 22q11.2 Foundation. The main outcome was the Childhood Sleep Habits Questionnaire (CSHQ). RESULTS: Scores on the CSHQ demonstrated clinically significant sleep problems in 29 of the 30 children. When compared with previously reported normative values for typically developing children of the same age, children with 22q11DS had significantly greater sleep problems. Only 30% of children had previously undergone sleep study. While about half of children had tried a medication for sleep, it usually was not felt to be helpful. In contrast, parents reported that behavioral interventions, such as consistent bedtime routine and appropriate sleep environment, were helpful. This is one of the first studies to specifically address sleep problems other than obstructive sleep apnea in children with 22q11DS. CONCLUSIONS: The findings suggest children with 22q11DS may have a higher risk of experiencing clinical sleep problems, compared to typically developing children. Consideration of additional screening and treatment of sleep disorders in children with 22q11DS is warranted.

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.