The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis. To date, only one large French Canadian family and a Finnish woman have been reported with the condition. In both, intragenic duplication encompassing exons 3-5 of the RUNX2 gene was identified. We describe a new, three-generation family with clinical features of MDMHB and an intragenic tandem duplication of RUNX2 exons 3-6. Dental problems were the primary presenting feature in all four affected individuals. We compare the features in our family to those previously reported in MDMHB, review the natural history of this condition and highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies.

How can general paediatric training be optimised in highly specialised tertiary settings? Twelve tips from an interview-based study of trainees.

OBJECTIVES: Both general and subspecialty paediatric trainees undertake attachments in highly specialised tertiary hospitals. Trainee feedback suggests that mismatches in expectations between trainees and supervisors and a perceived lack of educational opportunities may lead to trainee dissatisfaction in such settings. With the 'Shape of Training' review (reshaping postgraduate training in the UK to focus on more general themes), this issue is likely to become more apparent. We wished to explore the factors that contribute to a positive educational environment and training experience and identify how this may be improved in highly specialised settings. METHODS: General paediatric trainees working at all levels in subspecialty teams at a tertiary hospital were recruited (n=12). Semistructured interviews were undertaken to explore the strengths and weaknesses of training in such a setting and how this could be optimised. Appreciative inquiry methodology was used to identify areas of perceived best practice and consider how these could be promoted and disseminated. RESULTS: Twelve best practice themes were identified: (1) managing expectations by acknowledging the challenges; (2) educational contracting to identify learning needs and opportunities; (3) creative educational supervision; (4) centralised teaching events; (5) signposting learning opportunities; (6) curriculum-mapped pan-hospital teaching programmes; (7) local faculty groups with trainee representation; (8) interprofessional learning; (9) pastoral support systems; (10) crossover weeks to increase clinical exposure; (11) adequate clinical supervision; and (12) rota design to include teaching and clinic time. CONCLUSIONS: Tertiary settings have strengths, as well as challenges, for general paediatric training. Twelve trainee-generated tips have been identified to capitalise on the educational potential within these settings. Trainee feedback is essential to diagnose and improve educational environments and appreciative inquiry is a useful tool for this purpose.

Early-onset bilateral cerebral arteriopathies: Cohort study of phenotype and disease course.

OBJECTIVE: To describe characteristics of young children with arterial ischemic stroke (AIS) and bilateral cerebral arteriopathies. METHODS: Retrospective review of clinical features, course, and outcome. Neuroimaging was analyzed for infarct pattern, cerebrovascular diagnosis (anatomic/Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation [CASCADE] criteria), and disease progression. RESULTS: In the 31 children (median age, 18 months), presentations included acute hemiparesis (n=23) and focal seizures (n=12). Seven had systemic arterial disease; 13 had cardiac abnormalities. Twenty had recurrent AIS or transient ischemic attack (after median of 3 months); 16 had >1 recurrence. Median modified Rankin Scale score was 3, with motor impairments in 20, cognitive impairments in 11, and seizures in 7. At presentation, 17 had old and acute infarcts. Twenty-five had high signal in white matter. A total of 13/23 reimaged patients accrued further infarcts over a median of 39 months. Arteriopathy involved the carotid circulation bilaterally in all; 6 had posterior circulation and 11 had extracranial involvement. Arteriopathy distribution was symmetric in 24/31. CASCADE categories were 3A in 19, 3B in 5, 3C in 5, and 7 in 2. After a median of 35 months, 14 had had progression of arteriopathy. Patients categorized as CASCADE 3A (moyamoya) had significantly shorter time to recurrence than other groups. CONCLUSION: Young children with bilateral cerebral arteriopathies (particularly meeting criteria for CASCADE 3A) have a malignant course, with frequent recurrent events, progressive disease, and poor outcomes. Current classifications are limited in characterizing disease in many cases. Symmetric involvement suggests these arteriopathies may be developmentally determined, while systemic involvement suggests potential genetic etiology.