New Insights into the Neuropsychological Profile and Intellectual Quotient Variability in Joubert Syndrome Compared to Other Congenital Cerebellar Malformations.

The neuropsychological characteristics of the cerebellar cognitive affective syndrome (CCAS) in congenital, non-progressive malformations of the cerebellum have been scarcely investigated, and even less is known for Joubert syndrome (JS), an inherited, non-progressive cerebellar ataxia characterized by the so-called molar tooth sign. The few studies on this topic reported inconsistent results about intellectual functioning and specific neuropsychological impairments. The aim of this research is to examine the neuropsychological profile of JS compared to other congenital cerebellar malformations (CM), considering individual variability of intellectual quotient (IQ) in the two groups. Fourteen patients with JS and 15 patients with CM aged 6-25 years were tested through a comprehensive, standardized neuropsychological battery. Their scores in the neuropsychological domains were inspected through descriptive analysis and compared by mean of MANOVA and ANOVA models, then replicated inserting IQ as covariate. The two groups showed a largely overlapping neuropsychological profile, consistent with CCAS. However, the JS group showed worse performance in visual-spatial memory compared to CM patients, although this difference was mitigated when considering IQ. These findings highlight a divergence between JS and other CM in visual-spatial memory, which might suggest a critical role of the cerebellum in recalling task-relevant memories and might inform rehabilitative interventions.

Challenges and resources in adult life with Joubert syndrome: issues from an international classification of functioning (ICF) perspective.

BACKGROUND: Joubert Syndrome (JS) is a rare inherited neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation (i.e. the molar tooth sign) and variable organ involvement. The aim of the present study was to describe functional limitations and disabilities in a large sample of adult patients with a diagnosis of JS. METHODS: We administered the International Classification of Functioning (ICF) checklist to thirty-six adult Italian patients with JS or their caregivers through telephone calls. RESULTS: None-to-mild impairment was documented for basic cognitive and mental functions, whereas severe deficit emerged for higher-order skills and language. A mismatch between individuals' capacity for daily activity and social participation and the actual performance in these fields emerged, suggesting that adults with JS may greatly benefit from external support from the caring environment. Indeed, specific facilitators were highlighted, including communication technologies as well as family members, healthcare professionals and peers support. Mild-to-severe barriers have been identified by adult patients with JS in the domains of services, systems and policies. CONCLUSIONS: These findings highlight challenges and barriers for adults with JS in areas of daily functioning that may be improved by investing in rehabilitation care models that embed social support programs and policies into clinical interventions.IMPLICATIONS FOR REHABILITATIONChildren with Joubert Syndrome, a child-onset rare inherited neurodevelopmental condition, are growing up and becoming adults; a life course approach in rehabilitation is needed;There is a substantial lack of information on the long-term adaptive daily functioning of children with a diagnosis of Joubert Syndrome;In this paper, the International Classification of Functioning (ICF) was applied to assess the daily functioning in people with JS;Severe deficits emerged for high-order skills and language, whereas the use of communication technologies and the engagement of family members were highlighted as key facilitators;These findings highlight the need for a change of paradigm in the care model of subjects with JS, with the embedding of social support in rehabilitation programs.

Goldenhar syndrome: the importance of an ophthalmological approach.

The article describes a case of Goldenhar syndrome that had been diagnosed by an ophthalmologist in a medical consultation by school bullying due to a choristoma. A 15-year-old male patient, who had a nodular lesion with hair in the inferior temporal corneal-limbo-conjunctival of the left eye, was reported. He also had a facial asymmetry, with mild mandibular hypoplasia and malformation of the left external ear, where only an auricular appendage was formed. He denied similar family history and the history of genetic diseases, but revealed that his mother had used ibuprofen during the first 3 months of pregnancy and had gestational diabetes mellitus. Excisional biopsy of the eye lesion was performed and revealed a dermoid cyst. After the exegesis and with adequate multidisciplinary monitoring, the patient reported being very satisfied with the aesthetic result, returning with more confidence to his daily activities. That was a typical case of Goldenhar syndrome that has remained undiagnosed and untreated for more than a decade due to a lack of diagnosis despite its classic presentation. The delay in the approach resulted in social stigma and profound psychosocial damage. The importance of disseminating the correct knowledge of this pathology and of having an early multidisciplinary approach in these patients is emphasized, since the impact on the quality of life is significantly high.

A variable presentation of Joubert syndrome: Case report and a brief review.

Joubert syndrome is a rare neurological manifestation usually present in late infancy or early childhood with characteristic episodes of abnormal breathing pattern along with the neurological and other systemic involvement.We report a case of confirmed Joubert syndrome present in the immediate neonatal period with isolated spells of oxygen desaturations not accompanied by the classically described breathing pattern and absent neurological symptoms causing delay in the diagnosis. Isolated oxygen desaturation episodes could be a presenting manifestation of Joubert syndrome in a neonatal period.

[Cat-eye syndrome (a psychiatric aspect)]. / Sindrom 'koshach'ikh glaz' (psikhiatricheskii aspekt).

Cat-eye syndrome is associated with abnormalities in chromosome 22. Based on the literature on genetic and clinical characteristics of the disease, three clinical cases observed by the authors at different times are analyzed. Mental retardation of different degree was observed in all cases and schizotypal personality disorder in one case. The latter case is described in detail. The patient's stress due to the mockery of peers and teenagers regarding the characteristics of the patient's features plays a considerable role in the exacerbation of mental illness. Early cosmetic surgical intervention (iris's coloboma removal) is necessary to prevent exacerbations of a mental illness and comfortable existence of the patient in the social environment.

Natural history of PHACE syndrome: A survey of adults with PHACE.

BACKGROUND: Awareness of PHACE syndrome has increased; however, little information exists regarding its natural history, especially in patients over the age of 18. We aim to describe the natural history of PHACE to enhance clinical management and counseling of patients. METHODS: A cohort of patients ≥ 18 years was identified through the PHACE Syndrome Registry and a Vascular Anomalies Clinic Database. A cross-sectional survey was designed after a review of the literature by PHACE experts (IF, JP, DS). Questions were selected by consensus, and the survey was conducted using the Qualtrics platform and via in-person interviews. A 75% response rate was found. RESULTS: Eighteen adults-17 females and one transgender male-completed the survey. Respondents ranged in age from 18 to 59, with 24 being the mean age. Eighty-nine percent reported experiencing headaches, and 17% reported experiencing acute but transient symptoms mimicking acute ischemic stroke, later diagnosed as atypical migraines. Thirty-three percent reported hearing loss, and 67% endorsed dental issues. One patient experienced two arterial dissections. Three-fourths who attempted conception were successful, and none of their children had clinical features of PHACE. Because results were based on a retrospective survey, data captured were prone to recall bias and not objective. Results were limited by a small sample size. CONCLUSIONS: Health care providers should be aware of a possible increased risk of neurovascular complications, including atypical migraines mimicking transient ischemic attacks and arterial dissection, in adults with PHACE. Heritability has not been demonstrated, and future studies are needed to assess the risk of infertility.

Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause.

BACKGROUND: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

Cognitive rehabilitation in a child with Joubert Syndrome: Developmental trends and adaptive changes in a single case report.

We report the clinical and rehabilitative follow up of M, a female child carrying a compound heterozygous pathogenic mutations in the TCTN1 gene and affected by Joubert Syndrome (JS). JS is a congenital cerebellar ataxia characterized by "the molar tooth sign" on axial MRI, a pathognomonic neuroradiological malformation involving the cerebellum and brainstem. JS presents with high phenotypic/cognitive variability, and little is known about cognitive rehabilitation programs. We describe the therapeutic settings, intensive rehabilitation targets and outcome indexes in M's cognitive development. Using a single case evidence-based approach, we attempt to distinguish the effectiveness of the intervention from the overall developmental trend. We assume that an adequate amount of focused, goal directed treatment in a relative short period of time can be at least as effective as one provided in longer time, and much less interfering with the child's everyday life. We conclude by discussing specific issues in cognitive development and rehabilitation in JS and, more broadly, in cerebellar malformations.

[Pay attention to patient's visual function in oculoplastic surgery for congenital blepharophimosis syndrome].

Blepharophimosis is characterized by the presence of a narrowed horizontal palpebral aperture, ptosis, epicanthus inversus, and telecanthus. Due to patient's eye deformity, both of his or her appearance and psychological development are affected. In some cases, blepharophimosis not only influence the appearance but also the visual development. Therefore, patients with blepharophimosis require to be evaluated the visual function before the surgery in order to prevent amblyopia. In this article, we conclude that we should pay close attention to patient's visual function before and after the surgery. The timing of surgery must weigh the balance between early surgery to prevent amblyopia and late surgery for more reliable ptosis measurement, which provides a better surgical outcome.

Complications of ichthyosis beyond the skin.

Although ichthyoses are noted for their skin features, like many dermatologic conditions, patients are often impacted in ways beyond the skin. Much has been described in recent years regarding quality of life and skin disorders. This is certainly the case for ichthyosis. For neonates or others with diffuse involvement of their skin, nutritional needs are often exceeding normal requirements. These can often result in growth abnormalities. Lastly, with specific subtypes of ichthyosis, compromise of tissues around the eyes and ears can be of concern to some patients. Certainly, some forms of ichthyosis are routinely complicated by such findings. It is important for practitioners caring for individuals with ichthyosis to have these issues in mind.

Tolerance of deviations in eye and mouth position.

OBJECTIVE: To develop and refine a technique for measuring the tolerance for deviations in facial appearance. DESIGN: A psychophysical method was administered using photocopies of altered facial photographs to measure tolerances for deviations in eye position and mouth angulation and judges' reaction time. METHODS: Stimulus photos were displayed as Kodachrome slides to 76 individuals grouped by their familiarity with craniofacial anomalies, i.e. dental professionals, orthodontic and craniofacial patients, also a group of normal patients. RESULTS: (1) Tolerance for deviation of facial appearance varies inversely with the magnitude of the physical deviations from normal; (2) tolerance varies directly as a function of assumed familiarity with deviation; (3) response and reaction time varied inversely with the tolerance for facial deviation. CONCLUSION: Significant differences in tolerance and reaction time were found among the groups and depended on whether an isolated feature was judged or if the feature was judged in the context of the whole face.

Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features.

Muscle-eye-brain disease (MEB) is an autosomal recessive congenital muscular dystrophy with ocular abnormalities and type II lissencephaly. MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene on chromosome 1q33. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan. The disease is characterized by altered glycosylation of alpha-dystroglycan. The clinical spectrum of MEB phenotype and POMGnT1 mutations are significantly expanded. We would like to present two cases with MEB disease with POMGnT1 mutations, whose clinical picture shows heterogeneity. The patient with R442H mutation had the classical form of the disease although the one with IVS17-2A-->G homozygous mutation had severe autistic features as the dominating presenting sign. These two cases represent different spectrums of one disorder. To the best of our knowledge, autistic features and stereotypical movements have not been included thus far as a part of broad and heterogeneous MEB spectrum.

Psychosocial distress associated with disfiguring eye conditions.

PURPOSE OF STUDY: Visible disfigurement is associated with a range of psychosocial difficulties; however, the problems encountered by patients with eye conditions are under-researched. This study aimed to establish the extent and type of psychosocial distress in this patient population, and to explore the extent to which patients' needs are currently met. METHOD: Standardised measures (anxiety, depression, appearance-related distress, and quality of life) and a semistructured interview (exploring individual experiences and satisfaction with care) were administered to 153 consecutive attenders at outpatient eye clinics in three different hospitals. Responses were analysed using descriptive statistics, multiple regression, and cluster analyses. RESULTS: Between 10 and 49% of the patient sample scored unfavourably on standardised measures in comparison with normative values. Cluster analyses revealed that more distressed patients typically exhibited higher levels of anxiety, depression, social anxiety, self-consciousness, and social avoidance. Quality of life scores were also less favourable. Distressed patients felt less well informed, less involved in their treatment, and less well supported in the clinic setting. Variability within the sample was high; however, the effects of the cause and duration of the condition were not significantly related to distress. Clinic staff identified a variety of constraints to meeting patients' need, including patient numbers, the lack of appropriate training, and the lack of referral possibilities. CONCLUSIONS: A considerable proportion of patients with disfiguring eye conditions experience high levels of psychosocial distress. Several options exist for ways in which patients' needs might more effectively be met within the constraints currently facing care providers.

Daily patterns of running wheel activity in male anophthalmic mice.

Circadian rhythms are generated by the suprachiasmatic nuclei (SCN) and synchronized (entrained) to environmental light-dark cycles by the retinohypothalamic tract (RHT), a direct pathway from the retina to the suprachiasmatic nuclei. In anophthalmic mice, the optic primordia are resorbed between embryonic days 11.5 and 13, before retinal ganglion cells emerge. Thus the retinohypothalamic tract, which is the primary "zeitgeber" for circadian rhythms in sighted animals, never forms, and there is no retinal or photic input to the circadian system. We have used wheel running activity, a highly consistent and reliable measure of circadian rhythmicity in rodents, to establish the properties of endogenous locomotor rhythms of anophthalmic mice. We have identified three subpopulations of anophthalmic mice: a) rhythmic with strong stable circadian period but significantly increased period length; b) rhythmic with unstable circadian period; and c) arrhythmic. Future correlation of locomotor rhythms with properties of the suprachiasmatic nuclei in these mice will clarify the relationship between generation and properties of circadian rhythms and the neuroanatomical, neurochemical, and molecular organization of the circadian clock.

Ocular defects in children and adolescents with severe mental deficiency.

To assess the need for eye care in children and adolescents with severe mental deficiency, a cross-sectional study of the prevalence and causes of ocular defects amongst these individuals was conducted. Two hundred and sixty residents in a mental handicap unit were examined from January 1992 to June 1993. It was found that there was an unusually high prevalence of severe visual impairment (25%), refractive errors (24%), squint (8%) and a number of organic ocular diseases (8%). All the patients studied were non-verbal and 18% of them were deaf. Only 23 patients could walk. The results emphasize the need for establishing an efficient system to provide regular ophthalmic care for children with severe mental deficiency.