[The challenges of managing thoracic pain in cystic fibrosis (CF)]. / Herausforderungen der Therapie thorakaler Schmerzen bei zystischer Fibrose (CF).

BACKGROUND: Cystic fibrosis (CF) is a rare genetic multisystemic disorder with progressive abdominal and pulmonary involvement. Pain is still an underestimated symptom in CF patients. METHODS: A comprehensive review of guidelines and scientific literature on the topic was performed and combined with findings from pain management in a young CF patient with progressive thoracic pain. RESULTS: German CF guidelines do not cover diagnosis and management of pain in these patients. Studies from Europe and the United States report interactions between intensity of pain and mortality in CF, but do not include data on the efficacy of pain management. These data and clinical observations of a CF patient with episodes of intense thoracic pain are used to illustrate the specific challenges in pain relief. CONCLUSION: Pain management in CF requires meticulous monitoring as well as an interdisciplinary approach and should be implemented in the German CF guidelines. The authors also want to suggest recommendations for the treatment of thoracic pain in CF. The range and severity of organ involvement complicates the use both of opioids and non-opioids. Especially opioid treatment carries the risk of hypoxia and opioid-induced constipation (OIC) and needs close medical supervision.

[Current Practice of Pre- and Postnatal Screening and Future Developments for Evidence Based Guidelines]. / Aktueller Stand und zukünftige Entwicklung der prä- und postnatalen Vorsorge- bzw. Screeninguntersuchungen ­ Evidenz tut Not.

Objectives: In this selective review we provide an overview of the current pre- and postnatal screenings up to 18 years established in Germany to inform physicians of different medical fields (gynecologists, pediatricians, general practitioners, other medical specialists who treat children, adolescents or pregnant females). Current State: Research on screening for different types of cancer has frequently failed to show any benefit. Thus, there is a need to broaden the evidence basis related to medical screenings especially for children and adolescents. Outlook: Potential future developments of pre- and postnatal screenings are illustrated including their social impact. The lack of an early detection of mental health problems is pointed out. An interdisciplinary collaboration and research is required to accumulate evidence with regard to medical screenings and to consider health economic and ethical aspects.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency.

Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.

Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.

['Cases against KiSS': a diagnostic algorithm for children with torticollis]. / 'Cases against KiSS': A Diagnostic Algorithm for Children with Torticollis.

In 1991, Biedermann coined the term "kinetic imbalance due to suboccipital strain" ("KiSS-syndrome"). He assumed a functional abnormality of the suboccipital-high cervical spine, resulting in positional preference of the infant;s head. A broad spectrum of symptoms and complaints have been attributed to "KiSS-Syndrome". Patients are advised to undergo manual therapy, with pressure applied locally in order to readjust the cervical spine. Life threatening side-effects have been published repeatedly. We present two infants with brain tumours who developed torticollis and further neurological findings such as ataxia and reflex differences. In both cases, symptoms caused by the tumour were interpreted as "KiSS-syndrome", and appropriate diagnostics and therapy were delayed for months. There is no scientific evidence for the actual existence of "KiSS-syndrome" as a clinical entity or for the positive effects of manual therapy. Approximately 12% of all infants <12 months show a positional preference of the head, about 8% present with body asymmetry. Whereas most cases are benign, there is a long list of serious differential diagnoses for torticollis in infants. We give an updated review of the literature regarding "KiSS-Syndrome" and discuss the differential diagnostics in infants with torticollis.

Scheie syndrome: enzyme replacement therapy does not prevent progression of cervical myelopathy due to spinal cord compression.

Hurler-Scheie syndrome is caused by alpha-l-iduronidase deficiency. Enzyme replacement therapy (ERT) can improve physical capacity and reduces organomegaly. However, the effect on bradytrophic connective tissue is limited. As intravenously administered enzyme cannot cross the blood-brain barrier, the therapy of choice for the more severe Hurler syndrome is haematopoietic stem cell transplantation (HCT). In the more attenuated Scheie syndrome, neurological impairment is less severe; therefore, ERT may be appropriate to treat these patients. Information on long-term outcome in Scheie patients undergoing ERT is scarce. We report a 38-year-old female Scheie patient who has been on ERT for 8 years. While non-neurological symptoms improved, she developed paresthesias in her hands and feet and progressive pain in her legs. Somatosensory evoked potentials were abnormal, suggesting dysfunction of the dorsal funiculus and lemniscus medialis. After 6 years of ERT, a spinal MRI showed dural thickening at the upper cervical spine. These soft-tissue deposits are presumably due to the accumulation of mucopolysaccharides. Intramedullary hyperintensities at the level of C1/2 revealed cervical myelopathy. An MRI before the start of ERT had shown milder spinal lesions. Cystic lesions in the white matter of the centrum semiovale due to dilated Virchow-Robin spaces were essentially unchanged compared with the MRI scan before ERT. Decompression of the spinal cord resulted in clinical improvement. In an adult patient with Scheie syndrome, ERT failed to prevent progression of cervical myelopathy. Clinical significance of cerebral changes is unclear. Whether early HCT or intrathecal ERT could have prevented these lesions remains speculative.

Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1. SMARCAL1 encodes an enzyme with homology to the SNF2 chromatin remodelling proteins. METHODS: To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, we characterised the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localisation, and chromatin binding of SMARCAL1 missense mutants. RESULTS: The SIOD associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localisation, chromatin binding, and enzymatic activity. Further, expressing SMARCAL1 missense mutants in Drosophila melanogaster showed that disease severity was inversely proportionate to overall SMARCAL1 activity. CONCLUSION: Our results show for the first time that SMARCAL1 binds chromatin in vivo and that SIOD arises from impairment of diverse SMARCAL1 functions.

Novel mutations in exon 6 of the GFAP gene affect a highly conserved if motif in the rod domain 2B and are associated with early onset infantile Alexander disease.

Alexander disease is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Mutations of the GFAP gene, encoding Glial Fibrillary Acidic Protein, have been recognized as the cause of Alexander disease. Glial Fibrillary Acidic Protein is the major intermediate filament protein in astrocytes, its functional rod domain is conserved in sequence and structure among other intermediate filament proteins. We report here two cases of infantile Alexander disease with early onset and severe course, caused by DE NOVO mutations A364 V and Y366C. Both affected GFAP residues are part of a highly conserved coiled-coil trigger motif in the C-terminal end of segment 2B, probably required for the stability of intermediate filament molecules. Comparable effects are seen with mutations of the corresponding residues of the gene coding for keratin 14, another intermediate filament, this further supports the hypothesis that these positions of the trigger motif are generally critical for a normal function of intermediate filaments.

Vaso-occlusion in Schimke-immuno-osseous dysplasia: is the NO pathway involved?

Schimke-immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder with the main clinical findings of spondyloepiphyseal dysplasia, nephrotic syndrome, and defective cellular immunity. Vaso-occlusive processes, especially generalized atherosclerosis, are a life-limiting complication in patients with severe SIOD. The nitric oxide synthase (NOS) oxidizes L-arginine to nitric oxide (NO). NO is a potent vasodilator with inhibitory effects on platelet aggregation and the development of atherosclerosis. We hypothesized that reduced NO production due to antagonism of NOS by asymmetric dimethylarginine (ADMA) would be a possible pathophysiological mechanism for vaso-occlusion in SIOD. We tested this hypothesis in 10 patients with SIOD and 10 age-matched healthy controls. Plasma and urine levels of nitrite and nitrate, the indicators of NO synthesis, and of ADMA, an endogenous NOS inhibitor, in children suffering from SIOD were not significantly different from those in the age-matched healthy controls. Our results suggest that the L-arginine/NO pathway is not altered in SIOD. Antagonism of NOS by ADMA does not seem to be the cause of premature general atherosclerosis in SIOD. The underlying pathology of vaso-occlusion in SIOD still remains unclear.

Glutaric aciduria I: creatine supplementation restores creatinephosphate levels in mixed cortex cells from rat incubated with 3-hydroxyglutarate.

The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still unclear. Some evidence exists for compromised energy generation in the brain of patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH glut) for 24h. In the present study we measured cellular contents of high energy phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a 24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut specifically led to a reduction of CP content in a dose-dependent manner, whereas concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP-concentration could be prevented by preincubation with the non-competitive NMDA-receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor associated ion channels may be opened due to a lack of energy inside the neurons caused by a reduction of CP. This is followed by membrane depolarization which could impair electrogenic creatine transport into the cell.

Altered levels of high-energy phosphate compounds in fibroblasts from different forms of neuronal ceroid lipofuscinoses: further evidence for mitochondrial involvement.

The pathogenesis of neurodegeneration in neuronal ceroid lipofuscinosis (NCL) is still not clear despite progress in mutation analysis of these diseases. We have recently observed anomalies at the level of the mitochondrial ATPsynthase (complex V of the respiratory chain) in fibroblasts from children with CLN1, CLN2, CLN3 and in an ovine model (OCL6). The measurements were carried out in vitro. If these alterations were of relevance in vivo as well, contents of high-energy phosphate compounds should be reduced. In the present study, we measured levels of creatine phosphate (CP), ATP, ADP and AMP in fibroblasts from children with CLN1, CLN2, CLN3 and in OCL6. ATP was reduced to about 50% of normal in CLN1, CLN2 and CLN3, ADP was about 30% of normal in these cells, and CP was 50% of normal in CLN1 and CLN2 but remained normal in CLN3. In fibroblasts of NCL-sheep, however, CP and ADP were increased to 690% and 220% of normal, respectively, while ATP remained normal. If the anomalies found in cellular energy metabolism in fibroblasts were expressed in neurons from NCL patients and NCL sheep 'slow-onset excitotoxicity' could occur leading to cellular dysfunction and eventually to cell death.

trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation.

Dominant mutations of GJB2-encoding connexin-26 (Cx26) have pleiotropic effects, causing either hearing impairment (HI) alone or in association with palmoplantar keratoderma (PPK/HI). We examined a British family with the latter phenotype and identified a new dominant GJB2 mutation predicted to eliminate the amino acid residue E42 (DeltaE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (DeltaE42, D66H and R75W) identified in individuals with PPK/HI, and another (W44C) present in individuals with non-syndromic HI on gap junctional intercellular communication. We expressed mutant Cx26 alone and together with the epidermal connexins Cx26, Cx37 and Cx43 in paired Xenopus oocytes, and measured the intercellular coupling by dual voltage clamping. Homotypic expression of each connexin as well as co-expression of wild-type (wt) Cx26/wtCx43 and wtCx26/wtCx37 yielded variable, yet robust, levels of channel activity. However, all four Cx26 mutants were functionally impaired and failed to induce intercellular coupling. When co-expressed with wtCx26, all four mutants suppressed the wtCx26 channel activity consistent with a dominant inhibitory effect. However, only those Cx26 mutants associated with a skin phenotype also significantly (P<0.05) inhibited intercellular conductance of co-expressed wtCx43, indicating a direct interaction of mutant Cx26 units with wtCx43. These results demonstrate, for the first time, a trans-dominant negative effect of Cx26 mutants in vitro. Furthermore, they support a novel concept suggesting that the principal mechanism for manifestation of dominant GJB2 mutations in the skin is their dominant interference with the function of wtCx43. This assumption is further corroborated by our finding that Cx26 and Cx43 focally colocalize at gap junctional plaques in affected skin tissue of two carriers of DeltaE42.

Lichen planus associated with milia.

The formation of milia is well recognized in both bullous and inflammatory dermatoses. There are several reports of milia developing in a rare variant of lichen planus pilaris known as lichen planus follicularis tumidus (LPFT), but the association of milia with other types of lichen planus (LP) has not been documented in the literature. We report five patients who developed milia during the course of either drug-induced or idiopathic LP and one in whom milia developed in a lichenoid tattoo reaction. Milia were noted to occur transiently during the resolving phase of LP. Most cases were severe enough to warrant treatment with systemic steroids. The association of milia with LP is not restricted to the rare clinical variant LPFT. We speculate that a severe lichenoid reaction with basal layer degeneration may precipitate the formation of milia in some cases of LP.

Upregulation of connexin 26 is a feature of keratinocyte differentiation in hyperproliferative epidermis, vaginal epithelium, and buccal epithelium.

In epidermis, it has been suggested, intercellular communication through gap junctions is important in coordinating cell behavior. The connexins, may facilitate selective assembly or permeability of gap junctions, influencing the distribution of metabolites between cells. Using immunohistochemistry, we have compared the distribution of connexins 26 and 43 with that of proliferating cells (Ki67 labeling) in normal epidermis, hyperplastic epidermis (tape-stripped epidermis, psoriatic lesions, and viral warts), and vaginal and buccal epithelia. Connexin 43 was abundant in spinous layers of all epidermal specimens and in vaginal and buccal epithelia. Connexin 26 was absent from the interfollicular and interductal epidermis of normal hair-bearing skin, and nonlesional psoriatic epidermis but present at very low levels in plantar epidermis. Connexin 26 was prominent in lesional psoriatic epidermis and viral warts and in vaginal and buccal epithelia. In three independent experiments connexin 26 appeared in a patchy intercellular distribution in the basal epidermis within 24 h of tape stripping, proceeding to more extensive distribution in basal and suprabasal layers by 48 h. The increase in connexin 26 preceded that in cell proliferation. In vaginal epithelium, buccal epithelium, and viral warts connexin 26 was restricted mainly to suprabasal, nonproliferating cells. In psoriatic lesional epidermis connexin 26 was also located mainly in suprabasal, nonproliferating cells. Connexin 26 was present in a patchy distribution in the basal layer of psoriatic lesional epidermis, but double labeling for connexin 26 and Ki67 showed that many connexin 26 positive basal cells were nonproliferative, suggesting that connexin 26 may be related to differentiation rather than to proliferation. These observations would be consistent with a role for connexin 26 containing gap junctions during both early and later stages of keratinocyte differentiation in hyperplastic epidermis and in vaginal and buccal epithelia.

An audit of the completeness of non-melanoma skin cancer registration in Greater Glasgow.

The incidence of basal cell carcinoma and squamous cell carcinoma (non-melanoma skin cancer) is increasing in the U.K., and the importance of this has been recognized in the 'Health of the Nation' target of halting the annual increase in the incidence of skin cancer by the year 2005. An accurate assessment of incidence is necessary both in meeting this target and in planning skin cancer services. We have examined the ways in which basal cell carcinoma and squamous cell carcinoma are diagnosed and treated in Greater Glasgow and have determined how many of these tumours are, recorded by the West of Scotland Cancer Registry. Our results show that there is under-registration of both basal cell carcinoma and squamous cell carcinoma. Overall, 39 of 127 basal cell carcinomas (31%; 95% confidence interval [CI] 23-39%) and 11 of 25 squamous cell carcinomas (44%; CI 26-63%) were not registered by the cancer registry. We also showed that dermatologists rarely treat clinically suspicious tumours without obtaining pathological proof of the diagnosis. Accurate data collection by selected representative cancer registries is suggested as a possible solution.