Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. Objective: Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab. Methods: We obtained in situ cytokine profiles. Results: PGLUs were triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1ß as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. Conclusions: PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation.

Dupilumab: Two sides of a side-effect.

The purported antiviral effect of dupilumab may be considered a positive side effect. Its mechanism, however, points to an underlying immunomodulation with potentially far-reaching consequences.

Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss.

BACKGROUND: Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown. OBJECTIVES: To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition. METHODS: Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. RESULTS: Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL. CONCLUSIONS: Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.

Identification of a novel sporadic U2HR pathogenic variant in a patient with Marie Unna hereditary hypotrichosis.

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair loss disorder characterized by coarse, wiry, and twisted hair developing during early childhood, and followed by progressive hair loss with puberty. We report a sporadic case of a 4-year-old boy with clinical features suggestive of MUHH, in whom we identified the new pathogenic variant c.67C>T; p.(Gln23*) in U2HR. This finding extends the known spectrum of U2HR variants underlying MUHH and increases genetic information for further genotype-phenotype correlation.

Hereditary fibrosing poikiloderma (POIKTMP syndrome) report of a new mutation and review of the literature.

Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a genodermatosis with autosomal dominant inheritance caused by mutations in FAM111B. We report another case with a new pathogenic variant and analyze all previously published 34 cases with a focus on sequence of clinical presentation and genotype-phenotype correlation. POIKTMP is characterized by marked age-dependent clinical expressivity. FAM111B encodes a catalytic nuclear protein, expressed in many tissues, which contributes to impaired DNA repair affecting multiple systems. Specific inhibition of catalytic activity might be a future strategy to halt progression of this otherwise untreatable disease. Given the relentless progression of the disease, it would make sense to start such treatment as early as possible. In order to achieve this objective, children with suspected POIKTMP should therefore undergo early imaging of all relevant organ systems.

Epidemiology of inherited epidermolysis bullosa in Germany.

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany. METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

Multicentric dermatofibrosarcoma protuberans in a child with severe combined immunodeficiency due to adenosine deaminase deficiency.

We report the case of a 4-year-old boy, post-human stem cell transplantation for severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency (ADA), who developed multiple dermatofibrosarcoma protuberans (DFSP). We hypothesize a role for chimerism leading to accumulation of toxic metabolites which can cause DNA strand breaks and inhibit lymphocyte activation. Patients with ADA-SCID should remain under lifelong dermatologic surveillance as DFSP lesions can be quite inconspicuous.

Long-term sirolimus treatment in blue rubber bleb nevus syndrome: Case report and review of the literature.

Blue rubber bleb nevus syndrome is a rare vascular syndrome characterized by continuous eruption of vascular nodules in the skin, mucous membranes, and solid organs due to somatic activating mutations of the angiopoietin receptor TEK gene. It may be complicated by acute life-threatening hemorrhage and localized intravascular coagulation. We report an 11-year-old girl with complicated blue rubber bleb nevus syndrome treated with sirolimus since the age of 2. We review the literature on sirolimus therapy for children with blue rubber bleb nevus syndrome.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

Late growth of infantile hemangiomas in children >3 years of age: A retrospective study.

BACKGROUND: The proliferative phase of infantile hemangiomas (IHs) is usually complete by 9 months of life. Late growth beyond age 3 years is rarely reported. OBJECTIVE: To describe the demographic and clinic characteristics of a cohort of patients with late growth of IH, defined as growth in a patient >3 years of age. METHODS: A multicenter, retrospective cohort study. RESULTS: In total, 59 patients, 85% of which were female, met the inclusion criteria. The mean first episode of late growth was 4.3 (range 3-8.5) years. Head and neck location (55/59; 93%) and presence of deep hemangioma (52/59; 88%) were common characteristics. Posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities (PHACE) syndrome was noted in 20 of 38 (53%) children with segmental facial IH. Systemic therapy (corticosteroid or ß-blocker) was given during infancy in 58 of 59 (98%) and 24 of 59 (41%) received systemic therapy (ß-blockers) for late IH growth. LIMITATIONS: The retrospective nature and ascertainment by investigator recall are limitations of the study. CONCLUSION: Late IH growth can occur in children after 3 years of age. Risk factors include head and neck location, segmental morphology, and involvement of deep dermal/subcutaneous tissues.

Combined neodymium-doped yttrium aluminum garnet laser and sclerotherapy in Gorham-Stout syndrome.

Bone involvement is relatively rare in vascular malformations. Gorham-Stout disease, also referred to as vanishing bone disease, is characterized by osteoclast activation and osteolysis caused by proliferating lymphatic endothelial cells. We present the case of a 12-year-old boy who had Gorham-Stout disease at the age of 8 years. The clinical course was complicated by pathological fractures and localized intravascular consumption coagulopathy. Sclerotherapy and embolization therapy led to normalization of the coagulation parameters and significant improvement of the clinical findings. We speculate that this effect may be attributable to the elimination of lymphatic endothelial cells.

Infantile haemangioma.

With a prevalence of 4·5%, infantile haemangiomas are the most common benign tumours of infancy, arising in the first few weeks of life and exhibiting a characteristic sequence of growth and spontaneous involution. Most infantile haemangiomas do not require therapy. However, to identify at-risk haemangiomas, close follow-up is crucial in the first weeks of life; 80% of all haemangiomas reach their final size by 3 months of age. The main indications for treatment are life-threatening infantile haemangioma (causing heart failure or respiratory distress), tumours posing functional risks (eg, visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face. Oral propranolol is now the first-line treatment, which should be administered as early as possible to avoid potential complications. Haemangioma shrinkage is rapidly observed with oral propranolol, but a minimum of 6 months of therapy is recommended.

Lesion Morphology in Multifocal Infantile Hemangiomas.

BACKGROUND/OBJECTIVES: Multifocal infantile hemangiomas (MIHs; previously called neonatal hemangiomatosis) can be associated with extracutaneous hemangiomas. We observed different morphologic types of hemangiomas in children with MIHs and sought to find out whether they are related to the clinical course. METHODS: This was a retrospective study of 103 infants with MIHs and a control group of 261 age-matched patients with solitary focal infantile hemangiomas (IHs) seen at an academic pediatric dermatology department between 2004 and 2014. RESULTS: Two morphologic subtypes of hemangiomas were identified: miliary focal hemangiomas (MFHs; small, lens shaped) in 58 of 103 MIH patients (56.3%), and classical nonmiliary focal IHs (NMIHs; larger, irregularly shaped) in 17 of 103 patients (16.5%). MIHs featuring both types (mixed type) were observed in 28 of 103 patients (27.2%). MFH lesions were significantly smaller (mean 5.3 mm [range 1-20 mm] vs 22.0 mm [range 2-100 mm]), more numerous (23.4 ± 27.3 [range 5-175] vs 7.4 ± 2.8 [range 5-15] p < 0.001), and occurred up to an older age (6.0 ± 5.8 months [range 0-27 months] vs 3.8 ± 2.6 months [range 0-9 months]) than NMIHs. There was a weakly positive correlation between the number and presence of extracutaneous IHs in children with MFHs. Significantly more children with MIHs were delivered preterm than those with solitary IHs. CONCLUSIONS: The number of IHs correlates inversely with their size. MFHs follow a clinical course different from that of classical IHs, are associated with prematurity, and may confer greater risk of extracutaneous hemangiomas. Miliary hemangiomas thus appear to present a separate IH subset requiring special attention.

Raynaud's syndrome in children: systematic review and development of recommendations for assessment and monitoring.

OBJECTIVES: To develop recommendations for investigation and monitoring of children with Raynaud's syndrome, based on paediatric evidence collated by a systematic review. METHODS: A systematic review was undertaken to establish the paediatric evidence for assessment and monitoring of Raynaud's syndrome. An expert panel including members of the Paediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. RESULTS: The expert panel recommended testing anti-nuclear antibody (ANA), more specific antibodies associated with connective tissue disease and nail-fold capillaroscopy in all children presenting with Raynaud's syndrome as data suggests these can be risk factors for evolution into a connective tissue disease. The frequency of follow-up recommended depends on presence of these risk factors with the aim to detect evolving connective tissue disease early in high risk individuals. Those with no abnormalities on capillaroscopy and negative autoantibodies were deemed low risk of progression, whereas those with ANA positivity, specific autoantibodies and/or nailfold capillary changes were deemed high risk and more frequent follow-up was recommended. CONCLUSIONS: Recommendations, primarily based on consensus opinion, were agreed regarding investigation and monitoring of children who present with Raynaud's syndrome. Further prospective studies are needed to better define the risk factors for progression to connective tissue disease.

Anatomical patterns of infantile hemangioma (IH) of the extremities (IHE).

BACKGROUND: From 18% to 30% of infantile hemangiomas (IH) are located on the extremities (IHE). They can be divided into localized, segmental, and minimal or arrested growth (IH-MAG) subtypes. OBJECTIVE: We sought to correlate localization of IHE with the anatomy of the arterial vascular supply. METHODS: All children with segmental IHE and IH-MAG presenting to our department of pediatric dermatology from 2002 to 2015 were evaluated. Hemangiomas were mapped and their patterns were analyzed. RESULTS: Most IHE were unilateral (105/109). Two thirds (68/109) were located on the upper, and one third (41/109) on the lower extremities. Distal locations were more frequently affected. Segmental IHE were more common (upper extremities 83.8%; lower extremities 56.1%) than IH-MAG (16.2% and 43.9%, respectively). Ulceration occurred in 5.5%. Localization of IHE was found to correspond to supply areas of embryonic arterial variants. LIMITATIONS: This was a retrospective study. Only segmental IHE and IH-MAG were evaluated. Angiographic studies were not performed. CONCLUSION: The location of IHE may be related to variant anatomy of arterial supply during embryo fetal development. We hypothesize that this contributes to temporary regional tissue hypoxia during early fetal development, which is a known stimulus for the proliferation of hemangioma stem cells.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis.

BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta-analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) 'pandemic influenza'. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Of 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64-1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44-1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71-1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55-0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54-0·85; P = 0·001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

Blood Pressure Monitoring During the Induction and Maintenance Period of Propranolol Therapy for Complicated Infantile Hemangiomas: A Prospective Study of 109 Infants.

BACKGROUND: Propranolol has become the first-line treatment for complicated infantile hemangiomas (CIHs) worldwide. Recommendations for monitoring infants undergoing propranolol therapy vary. Data on long-term blood pressure (BP) monitoring have not been reported before. OBJECTIVE: The objective of the current study was to monitor BP in full-term infants during the induction and maintenance phase of propranolol therapy. METHODS: BP was monitored prospectively in 109 infants (mean age 2.8 mos, range 1-5 mos) with CIHs during the induction (3-4 days in the hospital during up-dosing from 0.5 to 2.0 mg/kg/day) and maintenance (6 mos) phases of oral propranolol therapy. RESULTS: Four children were excluded from the study because of sinus bradycardia (n = 2 [1.8%]) or lethargy (n = 2 [1.8%]). Mean systolic BP (SBP) decreased by 5 mmHg with the increase in propranolol dosage. Low (<5th percentile) SBP or diastolic BP (DBP) was observed in 2 of 105 children (1.9%) each. During the maintenance phase, 2 of 105 children (1.9%) had occasional SBP readings of less than 70 mmHg. No hypotension was observed after the third month of therapy. Low DBP (<36 mmHg) was recorded in 16 (15.2%) children after the first month, in 8.6% after the second, and in 2.9% during the third and fourth months of therapy. No patients exhibited clinical hypotension, bradycardia, or other known side effects of propranolol. Clinical response to therapy was excellent. LIMITATIONS: Reference BP values were derived from published tables, not from an untreated control group. CONCLUSIONS: In healthy full-term infants, propranolol (2 mg/kg/day divided in three doses) is well tolerated. No clinically significant hypotension was observed. We conclude that for otherwise healthy infants, BP monitoring during long-term propranolol therapy for CIHs is not necessary.

Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study.

BACKGROUND: Safe and effective therapies are needed for pediatric patients with psoriasis. OBJECTIVE: The purpose of this study was to evaluate ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis. METHODS: Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg [≤60 kg], 45 mg [>60-≤100 kg], and 90 mg [>100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤60 kg], 22.5 mg [>60-≤100 kg], and 45 mg [>100 kg]) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician's Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60. RESULTS: At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs. LIMITATIONS: The study was small relative to adult trials. CONCLUSIONS: In this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year.