CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

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. TRIAL REGISTRATION NUMBER: NCT01565005.

Ciprofloxacin use in neonates: a systematic review of the literature.

BACKGROUND: ciprofloxacin has no marketing authorization for use in neonates worldwide but it is prescribed for the treatment of neonatal life-threatening infections, mainly in developing countries and in Europe. Given the concerns about its toxicity in this population and the necessity for its use in specific clinical situations, we conducted a systematic review of the use of ciprofloxacin in neonates. METHODS: we performed a systematic search of PubMed, Embase, and the Cochrane Database of Systematic Reviews and bibliographies of relevant articles. We included all studies, regardless of design, that reported efficacy, safety, and pharmacokinetics of ciprofloxacin for the treatment of any neonatal infectious condition. We excluded letters, editorials, preliminary reports, and abstracts. RESULTS: observational cohort studies, case reports, and descriptions of patient series account for all literature reviewed. Ciprofloxacin was administrated in neonates as a salvage therapy for sepsis due to multidrug-resistant strains or with signs of clinical deterioration under first-line antibiotic treatment. Initial administration was always intravenous with variable dosing schedule. Clinical response to treatment was estimated at 64% and 91% in 2 cohort studies, with a median of 83% in case series. Of the 14 case reports, 12 yielded positive clinical outcomes. No serious adverse events, particularly joint toxicity, were observed, although evaluation was predominantly clinical and follow-up limited to few months after the end of treatment. CONCLUSIONS: the current literature provides some information to support the use of ciprofloxacin in neonates. Additional high quality studies should be undertaken to provide reliable data on pharmacokinetics, efficacy, and long-term safety.