Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation.

BACKGROUND: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, hemorrhage, recurrent headaches, and focal neurologic deficits. These CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Three CCM loci have been identified, on chromosomes 7q21-22 (CCM1; Online Mendelian Inheritance in Man [OMIM] 116860), 7p13-15 (CCM2; OMIM 603284), and 3q25.2-27 (CCM3; OMIM 603285), and 3 genes have been cloned, KRIT1 on CCM1, MGC4607 on CCM2, and PDCD10 on CCM3. Mutations in KRIT1 account for more than 40% of CCMs. OBJECTIVE: To describe the results of a comprehensive evaluation of 5 Italian families affected with CCM. DESIGN: Clinical, magnetic resonance imaging, and KRIT1 gene analysis. SETTING: University academic teaching hospitals. PATIENTS: Fifteen patients with CCM diagnosed according to defined criteria and 45 at-risk, symptom-free relatives. RESULTS: Three novel and 2 described mutations were found in KRIT1. The families included 33 KRIT1 mutation carriers, 57.6% of whom had no symptoms. Magnetic resonance imaging revealed CCM lesions in 82.3% of symptom-free mutation carriers. CONCLUSIONS: The data confirm both incomplete clinical and neuroimaging penetrance in families with the KRIT1 mutation. This consideration is important in genetic counseling. Moreover, the data emphasize both the importance of magnetic resonance imaging in the diagnosis of CCM and the potential for DNA-based diagnosis to identify subjects at risk.

Migraine and tension headache in children under 6 years of age.

OBJECTIVE: To investigate the clinical features of idiopathic headache with early onset, whose presence is probably underestimated by parents and physicians and the influence of environmental and psychological factors on headache in children. METHODS: We report on a prospective longitudinal evaluation of 35 consecutive children referred to the Neuropsychiatry Departments of the Universities of Varese and Pavia (mean age at the first observation: 4 years and 7 months, range: 12 months-6 years; mean age at onset: 4 years and 2 months, range: 10 months-6 years) presenting with headache symptomatology. Mean duration of clinical follow-up: 9.5 months. The diagnosis based on the IHS criteria was then compared to the intuitive clinical diagnosis made in accordance with alternative case definitions. We examined our patients for the presence of early developmental disorders and interictal somatic disorders. We also studied the role of psychosocial factors at the onset and in the course of headache. DIAGNOSIS: migraine without aura in two cases, episodic tension headache in four cases, migrainous disorders not fulfilling above criteria in eight cases, headache of the tension-type not fulfilling above criteria in 12 cases and headache not classifiable in nine cases. Clinical features of headache are described in the text. Early developmental disorders (0-2 years), such as eating difficulties and sleep disorders, were detected in 18/35 children. Among patients older than 2 years, we also detected interictal somatic disorders (20 cases) such as sleep disorders, eating difficulties, enuresis and idiopathic vomiting. In 14/35 subjects, we identified psychosocial components playing a significant role at the onset of, and during, the headache. CONCLUSIONS: A better clinical definition of the disorder would make it easier to identify very young affected children and consequently to plan more specific therapeutic interventions, taking into account environmental and psychological factors. A diagnosis of idiopathic headache becomes particularly significant: according to our cases, despite their being limited in number, migraine and tension headache can be considered also as indices of individual or family related problems requiring appropriate psychiatric or psychological intervention. This stresses the need for a multidisciplinary team of specialists that would include a psychologist/ psychiatrist or headache specialist with specific training in psychiatry.