Natural history of KBG syndrome in a large European cohort.

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Mood Stabilizers in Children and Adolescents With Autism Spectrum Disorders.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders including autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified as to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. All these categories are grouped together in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, classification under the category of Autism Spectrum Disorders.Behavioral disorders including irritability, attention-deficit/hyperactivity disorder (ADHD) symptoms, and aggression are additional symptoms found in up to 20% of children and adolescents with ASD and require careful evaluation for appropriate treatment. Attention-deficit/hyperactivity disorder is defined by impaired attention, hyperactivity, and impulsivity, whereas ASD is defined by social dysfunction, communicative impairment, and restricted/repetitive behaviors. They should be distinctly evaluated in children and adolescents with ASD and intellectual disability in contrast to individuals without intellectual disability, because significant differences between these conditions exist. Mood disorders are also common in ASD and should be systematically investigated in this population of children and adolescents. Approximately 50% of children and adolescents with ASD receive medication for comorbid behavioral/ADHD and mood symptoms, mostly stimulants, antiepileptics and antipsychotics. Guidelines for the evaluation and treatment including medications for ADHD-like symptoms have recently been provided and should be carefully considered. Antiepileptic drugs are commonly used in ASDs with epilepsy, because seizures are associated with ASD in 10% to 30% of young patients, and as mood stabilizers. Lithium is another option for children and adolescents with ASD who present with symptoms of a mood disorder, such as elevated moods/euphoria, mania, and paranoia, whether accompanied or not by irritability. Experimental treatments are under investigation and currently include arbaclofen, a γ-aminobutyric acid agent, and N-acetylcisteine, a glutamate agent.

Private inherited microdeletion/microduplications: implications in clinical practice.

The introduction of array-CGH analysis is allowing the identification of novel genomic disorders. However, this new high-resolution technique is also opening novel diagnostic challenges when inherited private CNVs of unclear clinical significance are found. Oligo array-CGH analysis of 84 patients with mild to severe mental retardation associated with multiple congenital anomalies revealed 10 private CNVs inherited from a healthy parent. Three were deletions (7q31, 14q21.1, Xq25) and seven duplications (12p11.22, 12q21.31, 13q31.1, 17q12, Xp22.31, Xq28) ranging between 0.1 and 3.8Mb. Six rearrangements were not polymorphic. Four overlapped polymorphic regions to the extent of 10-61%. In one case the size was different between the proband and the healthy relative. Three small rearrangements were gene deserts. The remaining seven had a mean gene content of five (ranging from 1 to 18). None of the rearranged genes is known to be imprinted. Three disease-genes were found in three different cases: KAL1 in dupXp22.31, STS in another dupXp22.31 and TCF2 in dup17q12. The patient carrying the last duplication presents sex reversal, Peters' anomaly and renal cysts and the duplication is located 4Mb away from the HSD17B1 gene, coding a key enzyme of testosterone biosynthesis. Considering the overlap with polymorphic regions, size-identity within the family, gene content, kind of rearrangement and size of rearrangement we suggest that at least in five cases the relationship to the phenotype has not to be excluded. We recommend to maintain caution when asserting that chromosomal abnormalities inherited from a healthy parent are benign. A more complex mechanism may in fact be involved, such as a concurrent variation in the other allele or in another chromosome that influences the phenotype.