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Background Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. Methods 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. Results All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. Conclusion This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. [ABSTRACT FROM AUTHOR]

Objective: To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children. Design: We conducted a university hospital-based observational study. Methods:All patients with GD followed for more than 1 year between 2003 and 2013 (nZ60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD. Results:Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II. Conclusion: Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up. [ABSTRACT FROM AUTHOR]