Daniel Ebrahimi-Fakhari

Topical Rapamycin for Facial Angiofibromas in a Child with Tuberous Sclerosis Complex (TSC): A Case Report and Long-Term Follow-up

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement including facial angiofibromas that often appear in early childhood. Here we report the case of a 12-year-old girl with widespread disfiguring facial angiofibromas that were successfully treated with topical rapamycin, a mTOR inhibitor. A sustained remission of skin lesions was documented in detail over a 3-year follow-up. This case highlights the fact that topical rapamycin is a useful option in treating TSC-associated skin lesions. Especially in medically complex patients topical treatment may lessen the need for surgical interventions, reducing the risks of surgery, its adverse effects and permanent scarring. However, there is no standard dose or formulation at present. Topical rapamycin appears safe, but long-term maintenance therapy is necessary to prevent facial lesions from regrowth.

Dermatological manifestations of tuberous sclerosis complex (TSC)

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement that frequently occurs in early childhood. Dermatologic manifestations include facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas. The International TSC Consensus Conference in 2012 provided guidelines for standardized baseline evaluation and follow‐up. Detailed clinical dermatological evaluation at the time of diagnosis and annual skin examination is recommended for both pediatric and adult populations. The onset of dermatological manifestations is clearly age‐related. However, dermatologists also have to assess for clinical manifestations beyond their own specialty. With advances in genetics and the advent of mTORC1 inhibitors, new specific therapeutic options have become available for TSC patients with skin manifestations. Early intervention is commonly recommended for symptomatic, rapidly evolving, disfiguring, or debilitating lesions. The consensus guidelines recommend “treatment as appropriate for the lesion and clinical context” and suggest the use of surgical excision, laser therapy, or topical mTORC1 inhibitors. Topical mTORC1 inhibitors present a useful option for TSC‐associated skin lesions, particularly in medically complex patients. They may prevent or reduce the risks of subsequent surgeries and permanent scarring.

Ante-, peri- and postnatal factors associated with intraventricular hemorrhage in very premature infants

BACKGROUNDnIntraventricular hemorrhage (IVH) is one of the most serious complications in preterm infants and is associated with neurological sequelae and mortality. Over the past few decades, the rate of IVH has decreased due to improved neonatal intensive care. However, up to 15-25% of very and extremely premature infants (<32 and <28weeks of pregnancy (WOP) respectively) still suffer from IVH.nnnSTUDY PURPOSEnThe aim of this study was to perform an updated, multicenter analysis to identify ante-, peri, and postnatal factors other than gestational age/birth weight associated with IVH of any grade in a large cohort of very and extremely premature infants.nnnMETHODSnWe performed a retrospective analysis in a prospectively conducted multicenter cohort study between 01/01/1998-31/12/2012 at 5 level 3 perinatal centers. All relevant ante-, peri- and neonatal data were collected and univariate as well as multivariate logistic regression analysis was performed.nnnRESULTSn765 inborn infants with a gestational age<32 WOP were enrolled into this study (369 (48.2%) female; 396 (51.8%) male). Birth weight ranged from 315g to 2200g (mean 1149.7g, SD 371.9g); 279 (36.5%) were born ≤27+6 WOP and 486 (63.5%)≥28+0 WOP. IVH was seen in 177 (23.1%) patients. Multivariate analysis revealed that in addition to higher gestational age (OR 0.7, CI [0.6-0.8]), antenatal steroid treatment (OR 0.3, CI [0.2-0.6]) and caesarian section without uterine contraction (OR 0.6, CI [0.4-0.9]) were associated with a lower rate of IVH while RDS (OR 5.6, CI [1.3-24.2]), pneumothorax (OR 2.8, CI [1.4-5.5]) and use of catecholamines (OR 2.7, CI [1.7-4.5]) were associated with an increased risk of IVH. After exclusion of gestational age and birth weight from multivariate analysis, early onset sepsis (OR 1.6, CI [1.01-2.7]) and patent ductus arteriosus (OR 1.9, CI [1.1-3.1]) were associated with a higher rate of IVH. In addition, univariate analysis revealed that Apgar scores at 5min (p<0.001), BDP/ROP/NEC (p<0.001), mechanical ventilation (p<0.001) and inhalative nitric oxide (p<0.001) were significantly associated with IVH.nnnCONCLUSIONSnOur comprehensive analysis demonstrated that the occurrence of IVH in very premature infants is significantly associated with ante-, peri- and postnatal factors being either related to the degree of immaturity or indicating a critical clinical course after birth. The analysis reiterates the necessity for a very close cooperation between obstetricians and neonatologists to reduce the incidence of IVH in this susceptible cohort.

Optimized care in Patients with Rare Diseases: TSC at the Center for Rare Diseases (ZSEUKS) at Saarland University Medical Center, Germany

Providing comprehensive medical care for patients with rare diseases is both challenging and rewarding. We will give a short summary of the most relevant medical issues pertinent to this subject, and will illustrate some of these issues by sharing our experience in the care of patients with TSC disease.

Nucleated red blood cells and serum lactate values on days 2 and 5 are associated with mortality and morbidity in VLBW infants

SummaryAimTo correlate nucleated red blood cell counts and serum lactate concentrations on dayxa02 andxa05 of life with morbidity and mortality in very low birth weight infants and to determine corresponding cutoff values.MethodsRetrospective analysis in axa0cohort of very low birth weight infants.Results250 very low birth weight infants were included in this study. Gestational age ranged from 23 to 35xa0weeks (mean 29.04) and birth weight was 320–1500u202fg (mean 1047.9). 55 (22%) patients developed intraventricular hemorrhage, 55 (22%) bronchopulmonary dysplasia, 12 (4.8%) periventricular leukomalacia, 93 (37.2%) retinopathy of prematurity, and 1 (0.4%) necrotizing enterocolitis. Mortality rate was 25/250 (10%). Nucleated red blood cells and serum lactate on dayxa02 of life were associated with mortality (pu202f<u20090.001). Serum lactate on dayxa05 of life demonstrated an association with retinopathy of prematurity (pu202f=u20090.017), bronchopulmonary dysplasia (pu202f=u20090.044), and intraventricular hemorrhage (pu202f<u20090.001). Cutoff values predicting mortality were >89.5 nucleated red blood cells/100 leucocytes (sensitivity 68.2%, specificity 89.0%) and serum lactate concentrations >8.5u202fmmol/l (sensitivity 69.6%, specificity 93.5%) on dayxa02 of life.ConclusionWe conclude that both nucleated red blood cell count and serum lactate concentration are valuable biomarkers in predicting important outcome parameters in very low birth weight infants.ZusammenfassungZielZiel der Untersuchung war es die Normoblastenzahl und Serumlaktatkonzentration an Lebenstag 2 und 5 mit der Morbidität und Mortalität von very low birth weight-Neonaten zu korrelieren und Cut-off-Werte zu bestimmen.MethodikRetrospektive Analyse in einer Gruppe von very low birth weight-Neonaten.ErgebnisseInsgesamt 250 very low birth weight-Neonaten wurden in die Studie eingeschlossen. Das Gestationsalter reichte von 23 bis 35 Schwangerschaftswochen (Mittelwert 29,04) und das Geburtsgewicht von 320 bis 1500xa0g (Mittelwert 1047,9). 55 (22xa0%) Patienten entwickelten eine intraventrikuläre Blutung, 55 (22xa0%) eine bronchopulmonale Dysplasie, 12 (4,8xa0%) eine periventrikuläre Leukomalazie, 93 (37,2xa0%) eine Frühgeborenen-Retinopathie und ein Patient (0,4xa0%) eine nekrotisierende Enterokolitis. Die Mortalität betrug 25/250 (10xa0%). Die Normoblasten und Serumlaktatkonzentrationen an Lebenstag 2 waren mit einer erhöhten Mortalität assoziiert (pxa0<xa00,001). Die Serumlaktatkonzentrationen an Lebenstagxa05 war mit einer erhöhten Rate an Frühgeborenen-Retinopathie (pxa0=xa00,017), bronchopulmonaler Dysplasie (pxa0=xa00,044) und intraventrikulärer Blutung (pxa0<xa00,001) assoziiert. Cut-off-Werte >xa089,5 Normoblasten/100 Leukozyten (Sensitivität 68,2xa0%, Spezifität 89,0xa0%) und Serumlaktatkonzentrationen >xa08,5xa0mmol/l (Sensitivität 69,6xa0%, Spezifität 93,5xa0%) an Lebenstag 2 wiesen auf eine erhöhte Mortalität hin.SchlussfolgerungWir schließen daraus, dass beide, die Normoblastenzahl als auch die Serumlaktatkonzentration, wertvolle Biomarker sind, die wichtige Outcome-Parameter von very low birth weight-Neonaten vorhersagen können.

Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study

BackgroundTuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited.MethodsProspective, national surveillance study in Germany over a 2-year-period (03/2015–02/2017) using current revised criteria for TSC. Patients up to the age of 18xa0years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data.ResultsIn total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6xa0months (range: 5xa0months before birth – 197xa0months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7xa0months) and 26.7% met criteria for a possible diagnosis (median age: 3xa0months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11xa0months with a range of 0 to 197xa0months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760–1:13.520 live births in Germany.ConclusionsThis is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6xa0months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

Diagnosis and Treatment of Tuberous Sclerosis Manifestations in Children: A Multicenter Study

Abstract Tuberous sclerosis complex (TSC) is a genetic disease with a significant morbidity and mortality. We conducted a retrospective analysis of two cohorts (Vall d’Hebron University Hospital [HVH], Barcelona, Spain, 1982‐2015, and at Saarland University Medical Center [UKS], Homburg, Germany, 1998‐2015) to assess prevalence and treatment of TSC associated manifestations and to evaluate if the follow‐up was in line with published recommendations. This was considered if more than 15% of patients did not receive adequate examination with regard to potential organ involvement. A definite diagnosis was made in 52 patients (96%), and a possible diagnosis was made in 2 patients (4%). Thirty‐four (63%) patients were from HVH and 20 (37%) from UKS. Median age at first presentation was 6 months (interquartile range: 0‐38 months), and median time of follow‐up was 6 years (interquartile range: 2‐13 years). Clinical symptoms that led to a diagnosis of TSC were cardiac rhabdomyoma (22/54), epilepsy (20/54), and cutaneous manifestations (4/54). Assessment of neuropsychiatric, renal, and ocular manifestations was inadequate in both hospitals, whereas cutaneous manifestation was inadequate at UKS only. Our data demonstrate insufficient examinations in a substantial number of TSC patients with regard to neuropsychiatric, renal, ocular, and cutaneous manifestations. The recently published guidelines may prove valuable in establishing a more comprehensive approach.

Off-Label Use of Ataluren in Four Non-ambulatory Patients With Nonsense Mutation Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory DMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18–26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

Birth weight, Apgar scores and gentamicin were associated with acute kidney injuries in VLBW neonates requiring treatment for patent ductus arteriosus

We assessed the risk factors for transient acute kidney injury in very low birth weight (VLBW) infants treated for patent ductus arteriosus (PDA) using the serum creatinine‐based criteria in Kidney Disease: Improving Global Outcomes.

ESPED-Erhebung: TSC-Erkrankung bei Kindern und Jugendlichen: eine einjährige Interim-Analyse@@@ESPED-Survey: TSC-disease in children and adolescents: preliminary results from a German epidemiological survey

BACKGROUNDnTuberous sclerosis complex (TSC) disease is axa0rare genetic, multi-organ disorder characterized by the occurrence of multiple hamartoma.nnnMETHODSnIn cooperation with ESPED, Germany, axa0prospective, epidemiological study was performed to assess the incidence of newly diagnosed TSC disease in patients ≤18xa0years in Germany. Moreover, the following parameters were assessed: 1.xa0Age distribution at initial diagnosis; 2.xa0Percentage of patients with in utero diagnosis of TSC; 3.xa0Detailed description of pathological clinical findings; 4.xa0Results from genetic testing.nnnRESULTSnIn this one-year interim analysis, 84xa0electronic questionnaires were received, 17 of which did not contain complete sets of data and were not included in data analysis. Twenty-three of 67xa0questionnaires did not report TSC patients and 3xa0reports contained redundant data sets and were excluded. In total, 41xa0reports were included into data analysis (female: 23; male: 18); median age at first diagnosis was 6xa0months (range: 0-151xa0months). The three most common symptoms were: central nervous affection: 31/41xa0patients ((75.6u2009%); 29/31 with seizures); rhabdomyoma: in 20/41 (48.8u2009%); cutaneous affection: hypomelanotic maculae (white spots): 20/41 (48.8u2009%). The three following organ manifestations were seen most often in axa0comprehensive diagnostic work-up: rhabdomyoma: 23/41 ((56.1u2009%); cortical dysplasia: 22/41 (53.7u2009%); white spots): 20/41 (48.8u2009%). In 11/41xa0patients, cardiac rhabdomyoma were detected by ultrasonography prenatally. In 6xa0patients, axa0TSC-2 mutation was found while in 4xa0patients axa0TSC-1 mutation was noted; in 1xa0patient, genetic testing was negative.nnnCONCLUSIONSnBased on our preliminary findings, the annual incidence rate for TSC disease is estimated at approximately 1:12,300 live births, but this is axa0very rough approximation.ZusammenfassungGrundlagenBei der Tuberösen Sklerose Complex-Erkrankung (TSC) handelt sich um eine seltene, genetisch bedingte Multisystemerkrankung, die charakterisiert ist durch das Auftreten von Hamartomen.MethodikProspektive, deutschlandweite Erfassung der TSC-Neuerkrankungen bei Patienten ≤18xa0Jahren (revidierte Diagnosekriterien 2013) im Rahmen einer ESPED-Erhebung (Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland).Fragestellungen1.xa0Altersverteilung bei Erstdiagnose? Prozentsatz der Patienten, die bereits pränatal erkannt werden? 2.xa0Detaillierte Erfassung der klinischen, organspezifischen Symptomatik; 3.xa0Ergebnisse der Molekulardiagnostik: Verteilung TSC1/TSC2? 4.xa0Wie hoch ist die Häufigkeit der TSC-Erkrankung in Deutschland/Genetik der TSC-Erkrankung?ErgebnisseZum Zeitpunkt der Zwischenauswertung lagen bei 17 der 84xa0elektronischen Fallmeldungen noch keine ausgefüllten Fragebögen vor, so dass diese bisher noch nicht klinisch-statistisch ausgewertet werden konnten (Rücklaufquote: 79,8u2009%). Bei 23 der 67xa0Rückmeldungen handelte es sich um Falsch- und bei 3 um Doppelmeldungen, so dass insgesamt 41xa0vollständig ausgefüllte Fragebögen in die Analyse eingingen (Mädchen:xa023, Jungen:xa018). Das mediane Alter zum Zeitpunkt der Diagnosestellung betrug 6xa0Monate (Minimum: 0xa0Monate; Maximum 151xa0Monate). Die 3xa0häufigsten initialen, klinischen Symptome waren: zentralnervöse, zerebrale Affektionen: 31/41 der Fälle ((75,6u2009%); 29/31xa0Patienten mit Krampfanfällen); Rhabdomyome: 20/41 (48,8u2009%); Hautaffektion (hypomelanotische Flecken/„white spots“: 20/41 (48,8u2009%)). Bei 11 der 41xa0Patienten wurde bereits intrauterin die Verdachtsdiagnose einer TSC-Erkrankung aufgrund des Vorliegens von kardialen Rhabdomyomen gestellt.Im Rahmen der weitergehenden Diagnostik wurden folgende 3xa0Organmanifestationen am häufigsten festgestellt: Kardiale Rhabdomyome: 23/41 (56,1u2009%); Kortikale Dysplasien: 22/41 (53,7u2009%); Hypomelanotische Flecken („white spots“): 20/41 (48,8u2009%). Bei 11xa0Patienten lagen die Ergebnisse der genetischen Diagnostik vor: 6xa0TSC-2 Mutationen, 4xa0TSC-1 Mutationen; einmal negative genetische Diagnostik.SchlussfolgerungenDie Inzidenz der TSC-Neuerkrankungen kann aufgrund der von uns erhobenen Daten zum jetzigen Zeitpunkt noch nicht gut abgeschätzt werden; bis jetzt ist für den Zeitraum 03/2015–02/2016 aufgrund unserer Daten mit einer Inzidenz von TSC-Neuerkrankungen für den Zeitraum 03/2015–02/2016 von rund 1:12.300 Geburten zu rechnen.SummaryBackgroundTuberous sclerosis complex (TSC) disease is axa0rare genetic, multi-organ disorder characterized by the occurrence of multiple hamartoma.MethodsIn cooperation with ESPED, Germany, axa0prospective, epidemiological study was performed to assess the incidence of newly diagnosed TSC disease in patients ≤18xa0years in Germany. Moreover, the following parameters were assessed: 1.xa0Age distribution at initial diagnosis; 2.xa0Percentage of patients with in utero diagnosis of TSC; 3.xa0Detailed description of pathological clinical findings; 4.xa0Results from genetic testing.ResultsIn this one-year interim analysis, 84xa0electronic questionnaires were received, 17 of which did not containn complete sets of data and were not included in data analysis. Twenty-three of 67xa0questionnaires did not report TSCn patients and 3xa0reports contained redundant data sets and were excluded. In total, 41xa0reports were included into datan analysis (female: 23; male: 18); median age at first diagnosis was 6xa0months (range: 0–151xa0months). The three mostn common symptoms were: central nervous affection: 31/41xa0patients ((75.6u2009%); 29/31 with seizures); rhabdomyoma: in 20/41n (48.8u2009%); cutaneous affection: hypomelanotic maculae (“white spots”): 20/41 (48.8u2009%). The three following organn manifestations were seen most often in axa0comprehensive diagnostic work-up: rhabdomyoma: 23/41 ((56.1u2009%); corticaln dysplasia: 22/41 (53.7u2009%); “white spots”): 20/41 (48.8u2009%). In 11/41xa0patients, cardiac rhabdomyoma were detected byn ultrasonography prenatally. In 6xa0patients, axa0TSC-2 mutation was found while in 4xa0patients axa0TSC-1 mutation was noted; in 1xa0patient, genetic testing was negative.ConclusionsBased on our preliminary findings, the annual incidence rate for TSC disease is estimated at approximately 1:12,300 live births, but this is axa0very rough approximation.