Tuomas Klockars

CLN5 , a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births. They are characterized by accumulation of autofluorescent lipopigments in various tissues. Several forms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separate genetic loci. All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death. One of the subtypes, Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects children at 4–7 years of age. The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myoclonia and seizures. We have previously reported linkage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region. Here, we report the positional cloning of a novel gene, CLN5, underlying this severe neurological disorder. The gene encodes a putative transmembrane protein which shows no homology to previously reported proteins. Sequence analysis of DNA samples from patients with three different haplotypes revealed three mutations; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.

Embryology and epidemiology of microtia.

The auricle derives from six hillocks arising from the first and second branchial arches. Different hillocks give rise to different parts of the pinna. In the course of embryonic development, the auricle migrates postero-cranially as the mandible enlarges. Auricular malformations, such as microtia, are thought to be related to cell death of the first and second arch derivatives. The prevalence and characteristics of microtia vary in different populations. The prevalence ranges from 0.83 to 17.4 per 10,000. Microtia is more common in males, and right-sided dominance varies from 57 to 67%. The prevalence of aural atresia or stenosis varies from 55 to 93%. Microtia has been associated with numerous risk factors including race and gender. Genetic factors are likely to have an effect at least in some patients with microtia.

Early placement of ventilation tubes in cleft lip and palate patients: does palatal closure affect tube occlusion and short-term outcome?

OBJECTIVES Otitis media with effusion is almost universal in children with cleft palate due to the poor function of the Eustachian tube. Our study investigates the functioning of ventilation tubes placed at the time of primary cleft surgery (4 months of age) and at the time of secondary surgery (12 months of age). We compared two different surgical protocols: (Leg A) closure of the lip and soft palate at the age of 3-4 months (primary surgery) and closure of the hard palate at the age of 12 months (secondary surgery), and (Leg C) closure of the lip at the age of 3-4 months (primary surgery) and closure of the hard and soft palate at the age of 12 months (secondary surgery). METHODS A retrospective review of the medical records of 97 Finnish children with unilateral cleft lip and palate (UCLP) included in the Scandcleft study and randomized into two groups. RESULTS The majority (63%) of cleft (lip and) palate children benefit from early placement of ventilation tubes, and this group is even larger with early closure of the soft palate (86%; p=0.02). Closure of the soft palate at four months of age also reduces the frequency of OME in ears with the tube extruded or occluded, thus indicating better function of the Eustachian tube (p=0.02). CONCLUSIONS Early tympanostomy tube placement should be considered in children with cleft lip and palate, even prior to palatal closure.

Pediatric tongue-tie division: Indications, techniques and patient satisfaction

OBJECTIVE To study the characteristics and outcome of paediatric tongue-tie division. PATIENTS AND METHODS Retrospective analyses of 317 paediatric tongue-tie divisions (frenotomy or frenuloplasty). RESULTS Based on a questionnaire returned by 159 (51%) of patients (or guardians) the most common indication was speech/articulation problems (64%). Other indications included restricted movement (18%) and lactation/nutrition problems (8%). 84% of patients (or guardians) reported benefit from the operation. The initial surgical technique was frenotomy (no or local anaesthesia) for 34%, frenotomy (general anaesthesia) for 16%, frenuloplasty (no or local anaesthesia) for 5% and frenuloplasty (general anaesthesia) for 46% of the patients. Almost one-third of children treated with frenotomy under no or local anaesthesia needed re-operation compared to one out of 181 (0.6%) treated with frenotomy or frenuloplasty under general anaesthesia. There were no postoperative complications. CONCLUSIONS Frenotomy under no or local anaesthesia is safe and cost-effective, but one-third of children need re-operation. Adequate division of the frenulum is more important than the technique (frenuloplasty vs. frenotomy) used and seems to be easier to achieve under general anaesthesia.

Finnish familial Meniere disease is not linked to chromosome 12p12.3, and anticipation and cosegregation with migraine are not common findings

Purpose: To study the inheritance and characteristics of familial Meniere disease in Finland and genetic linkage to the previously proposed locus on chromosome 12p12.3.Methods: Sixteen Meniere families recruited from Kainuu Central Hospital and Helsinki and Oulu University Hospitals in the period 2001–2004 were reevaluated in 2009 using hospital records and mailed questionnaire forms. Ten highly polymorphic microsatellite markers were selected from the area of chromosome 12p12.3 and studied for linkage using the GENEHUNTER protocol.Results: The families showed autosomal dominant inheritance without cosegregation with migraine. Anticipation was seen only in one family, and in the rest of the families, the age of onset varied randomly among generations and individuals. The severity of the disease was not related to descending generations. None of the maximum logarithm of odds (LOD)/heterogeneity LOD scores in the analysis of chromosome 12p12.3 in Finnish Meniere families reached a significant value of 3.0 (maximum cumulative LOD score: −7.29, heterogeneity LOD: −0.95, α = 0.4).Conclusions: Families affected by Meniere disease are highly heterogeneous. Migraine, age at onset, anticipation, or penetrance was not a shared feature. The findings support the multifactorial nature of the disease and indicate that genetic heterogeneity exists within familial Meniere disease.

Familial Zenker's diverticulum

Conclusion. The aetiology of Zenkers diverticulum is likely to be multifactorial. The geographical and racial variation in the prevalence and the rare familial cases suggest that genetic predisposition might have a role in the pathogenesis. The mode of inheritance in the rare possible familial cases seems to be autosomal dominant; recessive inheritance is non-existent or extremely rare. Objectives. To study the inheritance of Zenkers diverticulum. Subjects and methods. A detailed questionnaire concerning physical health and family history was sent to 122 patients with Zenkers diverticulum. Results. The prevalence of familial disease in Finland was found to be <2%. We found no evidence for genetic founder effect.

The learning curve in microtia surgery.

Reconstruction of the auricle is known to be complex. Our objective was to evaluate the improvement of the outcome of the lobulus-type microtia reconstruction. Patient satisfaction was also evaluated. There are no previous reports of the learning process in this field. Postoperative photographs of 51 microtia reconstructions were assessed and rated by a panel made up of six surgeons. The ratings were gathered to generate learning curves. Twenty-two patients assessed the outlook of their reconstructed ears, and the results were analyzed as a self-assessment group. The reliability of the rating by a panel was tested by intraclass correlations. There is a highly significant increasing trend in learning ( P = 0.000001). This trend is not constantly upward, and the steady state was not reached during the study. In the self-assessment group, females were significantly more critical than males ( P = 0.014). Intraclass correlation for six panel members was 0.90, and the rating was considered reliable. Thus, a long and gentle learning curve does exist in microtia reconstruction. To secure good quality and continuity, centralization of the operations and trainee arrangements are highly advisable. Outcomes of plastic surgery can reliably be rated by an evaluation panel.

Gene expression profiling analysis of the inner ear.

Recent developments in molecular genetics, including progress in the human genome project, have allowed identification of genes at an unprecedented rate. To date gene expression profiling studies have focused on identifying transcripts that are specifically or preferentially enriched within the inner ear on the assumption that they are more likely to be important for auditory and vestibular function. It is now apparent that some genes preferentially expressed in the cochleo-vestibular system are not crucial for hearing or balance or their functions are compensated for by other genes. In addition, transcripts expressed at low abundance in the inner ear are generally under-represented in gene profiling studies. In this review, we highlight the limitations of current gene expression profiling strategies as a discovery tool for genes involved in cochleo-vestibular development and function. We argue that expression profiling based on hierarchical clustering of transcripts by gene ontology, combined with tissue enrichment data, is more effective for inner ear gene discovery. This approach also provides a framework to assist and direct the functional characterization of gene products.

Juvenile nasopharyngeal angiofibroma: no evidence for inheritance or association with familial adenomatous polyposis

Juvenile nasopharyngeal angiofibromas (JNAs) are rare tumors with prominent vascularity and locally destructive growth. The pathogenesis of JNA is largely unknown. A causal association between JNA and familial adenomatous polyposis has been suggested. Twenty-one patients diagnosed with juvenile angiofibroma filled out a detailed patient questionnaire. No patients reported any relatives with nasopharyngeal angiofibroma or familial adenomatous polyposis. No significant regional clustering suggestive for founder effect could be identified. We believe that if there were a strong genetic predisposition or association with familial adenomatous polyposis, it should have been seen in this patient sample.

Second branchial cleft fistulae: Patient characteristics and surgical outcome

BACKGROUNDS Second branchial cleft anomalies predispose to recurrent infections, and surgical resection is recommended as the treatment of choice. There is no clear consensus regarding the timing or surgical technique in the operative treatment of these anomalies. Our aim was to compare the effect of age and operative techniques to patient characteristics and treatment outcome. METHODS A retrospective study of pediatric patients treated for second branchial sinuses or fistulae during 1998-2012 at two departments in our academic tertiary care referral center. Comparison of patient characteristics, preoperative investigations, surgical techniques and postoperative sequelae. RESULTS Our data is based on 68 patients, the largest series in the literature. One-fourth (24%) of patients had any infectious symptoms prior to operative treatment. Patient demographics, preoperative investigations, use of methylene blue, or tonsillectomy had no effect on the surgical outcome. There were no re-operations due to residual disease. Three complications were observed postoperatively. CONCLUSIONS Our patient series of second branchial cleft sinuses/fistulae is the largest so far and enables analyses of patient characteristics and surgical outcomes more reliably than previously. Preoperative symptoms are infrequent and mild. There was no difference in clinical outcome between the observed departments. Performing ipsilateral tonsillectomy gave no outcome benefits. The operation may be delayed to an age of approximately three years when anesthesiological risks are and possible harms are best avoided. Considering postoperative pain and risk of postoperative hemorrhage a routine tonsillectomy should not be included to the operative treatment of second branchial cleft fistulae.