Clinical Outcome of Children With Corpus Callosum Agenesis.

BACKGROUND: Agenesis of the corpus callosum is a rare congenital brain malformation that can be associated with other cerebral malformations and/or underlying genetic causes. Prenatal counseling is hampered due to the lack of reliable long-term data on neurodevelopmental outcome. METHODS: Since 2010, a total of 23 children with agenesis of the corpus callosum (mean age 3.8 years, range 0.7 to 9.7 years) were registered in our ACC outpatient clinic and diagnosed in a standardized manner; the data were analyzed retrospectively. Prenatal and postnatal imaging, associated malformations, genetic and clinical findings, and psychological testing (Bayley Scales, Kaufman Assessment Battery for Children II, Snijders-Oomen Non-verbal Test, Wechsler Preschool and Primary Scale I-III) were included. The clinical outcome was classified as "normal" (intelligence quotient 85 to 115, unremarkable motor skills), "moderate developmental delay" (intelligence quotient 70 to 85, mild motor abnormalities), and "severe developmental delay" (intelligence quotient less than 70, severe movement disorder). RESULTS: Isolated corpus callosum malformation was diagnosed in 15 of 23 (65%), associated cerebral malformations in four of 23 (17%), and associated cerebral malformations plus intracranial cyst in four of 23 (17%) children. Prenatal diagnosis changed in nine of 23 (39%) cases. Overall, a normal outcome or moderate or severe developmental delay was present in 15 of 23 (65%) or five of 23 (22%) or three of 23 (13%) children, respectively. Also six of eight children with associated cerebral malformations showed normal outcome. CONCLUSION: Our findings support the notion that developmental outcome is favorable in about two-thirds of children with prenatally diagnosed agenesis of corpus callosum. However, the individual outcome in children with agenesis of corpus callosum is difficult to predict. Even children with correctly characterized phenotypes show a variety of outcomes, making prenatal counseling challenging.

Familial Xp11.22 microdeletion including SHROOM4 and CLCN5 is associated with intellectual disability, short stature, microcephaly and Dent disease: a case report.

BACKGROUND: Two interstitial microdeletions Xp11.22 including the CLCN5 and SHROOM4 genes were recently reported in a male individual affected with Dent disease, short stature, psychomotor delay and minor facial anomalies. Dent disease, characterized by a specific renal phenotype, is caused by truncating mutations of CLCN5 in the majority of affected cases. CASE PRESENTATION: Here, we present clinical and molecular findings in a male patient with clinical signs of Dent disease, developmental delay, short stature, microcephaly, and facial dysmorphism. Using molecular karyotyping we identified a hemizygous interstitial microdeletion Xp11.23p.11.22 of about 700 kb, which was inherited from his asymptomatic mother. Among the six deleted genes is CLCN5, which explains the renal phenotype in our patient. SHROOM4, which is partially deleted in this patient, is involved in neuronal development and was shown to be associated with X-linked intellectual disability. This is a candidate gene, the loss of which is thought to be associated with his further clinical manifestations. To rule out mutations in other genes related to intellectual disability, whole exome sequencing was performed. No other pathogenic variants that could explain the phenotypic features, were found. CONCLUSION: We compared the clinical findings of the patient presented here with the reported case with an Xp11.22 microdeletion including CLCN5 and SHROOM4 and re-defined the phenotypic spectrum associated with this microdeletion.

Pontine Tegmental Cap Dysplasia in an Extremely Preterm Infant and Review of the Literature.

Pontine tegmental cap dysplasia is a rare hindbrain malformation syndrome with a hypoplastic pons, a tissue protrusion into the fourth ventricle, and cranial nerve dysfunction. We here report clinical, imaging, and genetic findings of the first extremely low-birth-weight preterm infant with pontine tegmental cap dysplasia born at 25 weeks of gestation and provide an overview of 29 sporadic cases. A prenatally diagnosed hypoplastic and rostrally shifted cerebellum was indicative of a hindbrain defect and later identified as an early sign of pontine tegmental cap dysplasia in our patient. The neonate exhibited severe muscle hypotonia, persistent thermolability, and clinical signs of an involvement of facial, cochlear, and hypoglossal nerves. Furthermore, paroxysmal episodes of agonizing pain with facial tics, tonic and clonic muscle contractions, blepharospasm, and singultus are highlighted as new phenotypic features of pontine tegmental cap dysplasia. With our report, we present a severe case of pontine tegmental cap dysplasia and provide a brief overview of current knowledge on this rare disease.

GLRB is the third major gene of effect in hyperekplexia.

Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and ß-subunits (GLRB) in a 2α(1):3ß configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.