Cutaneous infantile haemangioma (IH) occurs in 5-10% of neonates, with multiple IH (>1) in 30% of those1 . Expert opinion currently recommends routine liver ultrasound(USS) for five or more(5+ ) IH2,3 , and if hepatic haemangiomas(HH) are identified, to test thyroid function3 even if neonatal thyroid screening occurred. Supportive data from one cohort demonstrate associations between 5+ IH and HH1 , and between HH and adverse clinical outcomes (cardiac failure/hypothyroidism)4-6 .

DOI: 10.1111/bjd.19296 S. Polubothu N. McGuire L. Al-Olabi et al. Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi. https://onlinelibrary.wiley.com/doi/10.1111/bjd.18747 https://onlinelibrary.wiley.com/doi/10.1111/bjd.18762 (Mandarin) The above Plain Language Summary from the British Journal of Dermatology, published online on 03 February 2020 in Wiley Online Library (wileyonlinelibrary.com), and in print and online in issue 182.2, also translated into Mandarin in issue 182.2, has been withdrawn by agreement between the authors, the journal's editor-in-chief, John Ingram, the British Association of Dermatologists, and John Wiley & Sons Limited. Both the original Plain Language Summary and the Mandarin translation of the Plain Language Summary have been withdrawn. The Plain Language Summary incorrectly attributed authorship to the authors of the original article S. Polubothu N. McGuire L. Al-Olabi, et al. The Plain Language Summary was written by a BJD in-house dermatologist and not the authors. The authors of the original article were inserted to establish a link to the paper, and not to attribute authorship of the Plain Language Summary. The Plain Language Summary has now been withdrawn and replaced with a version provided by the authors. We apologise for this error, and have since changed the way our Plain Language Summaries are written and attributed.

BACKGROUND:Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. OBJECTIVES:To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations. METHODS:We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. RESULTS:Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare. CONCLUSIONS:CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

dear editor, Congenital hemidysplasia with ichthyosiform naevus and limb defects (CHILD) syndrome is a rare X‐linked dominant disorder caused by mutations in NSDHL.1, 2 This gene encodes the enzyme 3β‐hydroxylsterol dehydrogenase, which catalyses a step in the cholesterol biosynthetic pathway.1 Characteristic signs present at birth or in the first weeks of life, namely strikingly unilateral ichthyosiform skin lesions with a sharp midline demarcation, and ipsilateral limb defects (ranging from hypoplasia of the phalanges to absence of the entire extremity).1, 3 The face is usually spared. The central nervous system, lungs, heart and kidneys can also be involved.2 We report a case of CHILD syndrome without the characteristic hemidysplasia. A 7‐year‐old girl was referred to our department for evaluation of areas of persistently inflamed and hyperkeratotic skin. She was born at 35 weeks of gestation by caesarean section for breech presentation, without gross limb defects. Her medical history revealed a radiological diagnosis of spinal chondrodysplasia punctata with atlantoaxial subluxation and intermittent spinal compression, bilateral hip subluxation, severe neurodevelopmental delay, chronic lung disease requiring tracheostomy and night‐time ventilation, gastro‐oesophageal reflux and gastrostomy feeding. Brain magnetic resonance imaging had revealed general loss of white matter bulk but with no asymmetry. The skin lesions had been present from birth, and persistent symptoms were recurrent painful fissuring and pruritus. Cutaneous examination revealed inflammatory ichthyotic lesions along the lines of Blaschko on both upper limbs (right more than left), in the right groin, and diffusely on both cheeks. In addition, there were areas of persistent nonscarring alopecia bilaterally on the scalp, one circular and well circumscribed, and the other more diffuse, with no evidence of trichotillomania. Dysmorphic facial features included deep‐set eyes and epicanthic folds. Importantly, and compatible with previous reports,4 the patient's mother had similar but much milder linear hyperkeratotic skin lesions affecting the right arm and hand, but was otherwise unaffected (Fig. 1). Figure 1 (a–d) Clinical and radiological images. Large erythematous xerotic plaques in a linear distribution on both upper limbs, affecting the right groin and thigh, and diffusely bilaterally on the cheeks. (e, f) Small areas of nonscarring alopecia bilaterally ... Skin biopsy of affected skin from the patient showed features compatible with ichthyosiform dermatosis: acanthosis and extension of rete pegs of the epidermis, marked parakeratotic scaling with loss of the granular layer, occasional clusters of neutrophils, and perivascular and dermal lymphohistiocytic infiltrates (Fig. 2), but without the characteristic verruciform xanthoma of CHILD syndrome. Array comparative genomic hybridization analysis of peripheral blood leucocyte DNA was normal, excluding large copy number changes (resolution 150 kb). Sanger sequencing revealed a novel germline heterozygous microdeletion inducing a frameshift and premature stop codon at position 119 of a total translated length of 373 amino acids in NSDHL (c.357_358del, p.Arg119Serfs*1d), predicted damaging in silico. This mutation is compatible with the previously reported disease‐causing mutations in classical CHILD syndrome,1 and on the basis of current knowledge confirmed a genetic diagnosis of CHILD syndrome in both the patient and her mother. No other changes in the gene were identified. Previously reported mutations have principally been heterozygous nonsense or missense point mutations, and large heterozygous deletions have been described.3, 5 This novel microdeletion would be predicted to cause loss of function by truncating the protein before the catalytic site of the gene product. Figure 2 (a, b) Skin biopsy showing features compatible with ichthyosiform dermatosis: acanthosis and extension of rete pegs of the epidermis, marked parakeratotic scaling with loss of the granular layer, occasional clusters of neutrophils, and perivascular and ... Traditionally, management of skin lesions in CHILD syndrome has been difficult; however, Paller et al. recently reported an innovative and highly successful topical therapy in two patients – co‐application of cholesterol 2% and lovastatin 2% – based on the role of NSDHL in cholesterol metabolism.6 These results have been replicated in three further reports of patients using co‐application of cholesterol 2% and simvastatin 2%,7 and has been successfully trialled in our patient, with complete resolution of erythema and hyperkeratosis in the treated groin area. Two other conditions are interesting to consider in this atypical case (Table 1). Firstly, the recently described allelic disorder CK syndrome (MIM #300831), caused by milder mutations in NSDHL, is characterized by cortical malformations, typical facial features, asthenic body habitus and no described cutaneous phenotype. Our patient does not exhibit typical features of this syndrome. Secondly, Conradi–Hunermann–Happle (CHH) syndrome is an X‐linked dominant disorder caused by mutations in the emopamil‐binding protein gene (EBP), which governs the next step in the cholesterol biosynthetic pathway after NSDHL. The presence of chondroplasia punctata, intellectual disability and alopecia have all been described in CHH syndrome; however, disproportionate skeletal growth, growth deficiency, characteristic linear/whorled pigmentary lesions and cataracts were lacking in our patient. Furthermore, the histological features in this case support a diagnosis of CHILD syndrome and exclude a diagnosis of CHH. Table 1 Comparison of features of congenital hemidysplasia with ichthyosiform naevus and limb defects (CHILD) syndrome, Conradi–Hunermann–Happle (CHH) syndrome, CK syndrome and our patient A clear bilateral presentation in CHILD syndrome has been reported rarely before, once with characteristic skin lesions affecting the body folds in a near‐symmetrical distribution, associated with a novel missense mutation in NSDHL,8, 9 twice with contralateral linear skin lesions,1 once with bilateral, almost symmetrical, linear lesions on the extremities.10 Our case confirms this bilateral cutaneous presentation, emphasizes the significant inter‐ and intrafamilial variation, and extends the noncutaneous phenotype of CHILD syndrome.

BACKGROUND:Severe pediatric slow transit constipation (STC) is commonly due to intrinsic colonic neuromuscular disease. We sought to correlate neuromuscular histological phenotypes in pediatric STC with colonic manometric phenotypes using high-resolution manometry (HRM). We tested the hypothesis that failure of motor quiescence (FQ) between bisacodyl-induced high amplitude propagating sequences (HAPSs) might predict neuromuscular pathology.METHODS:Eighteen children (10 males, median age: 7.5 years) with refractory STC underwent stationary colonic HRM before segmental colonic resection. Six age-matched constipated children with normal colonic transit served as controls. Colonic resection specimens underwent histopathological analysis. Conventional manometric parameters and area under the curve (AUC) during a 1-min period following bisacodyl-induced HAPSs [PBAUC(1) ], as measure of FQ, were calculated.KEY RESULTS:Numbers of postbisacodyl HAPSs in descending and sigmoid segments were lower in patients than controls (P < 0.01, respectively). Low amplitude propagating sequences (LAPSs) were common prebisacodyl in controls and rare in STC (P < 0.001), whereas postbisacodyl LAPS were more common in STC (P < 0.001). Postbisacodyl, both retrograde propagating contractions and bursts of contractions were present in STC patients only (P < 0.001 and P < 0.01). Postbisacodyl simultaneous pressurization was seen only in STC (P < 0.05 and P < 0.001, in descending and rectosigmoid segments). Histological abnormalities were present in 17/18. Fourteen were neurogenic, one neuro-myogenic, and two myogenic. In segments with HAPS, PBAUC(1) was predictive of colonic neuropathy using a cutoff of 205 mmHg.s(-1) (Sensitivity 100%, specificity 86%, PPV92%, NPV100%).CONCLUSIONS & INFERENCES:PBAUC(1) is increased in multiple colonic segments in neuropathic pediatric STC and constitutes a sensitive and specific biomarker of neuropathy.

Background: The terminology applied to vascular anomalies has been variable in previously published literature making interpretation suboptimal. The International Society for the Study of Vascular Anomalies (ISSVA) has proposed a revised classification based on clinical features and histopathological findings. This classification is increasingly being accepted as clinically useful and a platform for future studies. Aims: To examine the extent to which the ISSVA classification can be practically applied to diagnostic histopathological specimens. Methods: Cutaneous vascular lesions received in a single paediatric pathology unit during a 2-year period (2004–5) were reviewed, including glucose transporter protein 1 (GLUT1) immunostaining where required, and lesions were reclassified according to the ISSVA classification. Results: 144 specimens were identified. Appropriate full clinical information was provided in only 17% of cases at submission. Infantile haemangiomas comprised 46% of cases, 18% of which were regressive type, initially inaccurately identified as vascular malformations before GLUT1 immunostaining. 30% of lymphatic malformations and all lymphovenous malformations were previously classified as vascular malformations, not otherwise specified. Conclusions: The ISSVA classification of vascular anomalies provides a useful framework for histopathologists to classify vascular anomalies. However, meaningful and appropriate use of such a system is dependent on the adequacy of clinical information provided and routine use of immunohistochemical markers.

MYCN amplification and 1p36 deletion are adverse prognostic factors in neuroblastoma, and rapid accurate determination of MYCN amplification is essential for risk stratification. MYCN copy number and 1p36 deletion status were determined by fluorescence in situ hybridization (FISH) and real time PCR in a diagnostic pathology laboratory setting on 35 consecutive patients with neuroblastoma. The PCR technique was technically successful in all cases and results were generally available within 24 hr of biopsy. There was no discordance between FISH and PCR results. Real time PCR is a reliable, accurate, and simple technique that can be applied to small neuroblastoma biopsies allowing rapid diagnosis.

Journal of Pediatric Gastroenterology and NutritionVolume 40, Issue 5 p. 650-650 Abstracts: 38th Annual Meeting of the European Society for Pediatric Gastroentrology, Hepatology and Nutrition: Porto, Portugal, June 1-4, 2005 GUT GRAFT VERSUS HOST DISEASE: THE ROLE OF INFECTION AND IMPLICATIONS FOR TREATMENT PG3-10 A Hassan, A Hassan Department of Immunology and Bone Marrow Transplant, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorM Elawad, M Elawad Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorD Rampling, D Rampling Department of Histopathology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorV Smith, V Smith Department of Histopathology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorP Veys, P Veys Department of Immunology and Bone Marrow Transplant, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorP Milla, P Milla Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this author A Hassan, A Hassan Department of Immunology and Bone Marrow Transplant, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorM Elawad, M Elawad Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorD Rampling, D Rampling Department of Histopathology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorV Smith, V Smith Department of Histopathology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorP Veys, P Veys Department of Immunology and Bone Marrow Transplant, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this authorP Milla, P Milla Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, United-KingdomSearch for more papers by this author First published: 01 May 2005 https://doi.org/10.1002/j.1536-4801.2005.tb01215.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume40, Issue5May 2005Pages 650-650 RelatedInformation

The diagnosis of pediatric tumors relies heavily on immunohistochemical staining of small tissue biopsies, since many entities share a "small blue cell" phenotype. More recently, molecular genetic analysis for detection of specific gene fusion products has become available. With the increased use of such molecular techniques, the authors have noted that tumors with proven molecular diagnoses can exhibit unusual patterns of immunohistochemical staining. This study examines pediatric tumors with a "small blue cell" phenotype in which molecular diagnoses were available where applicable. A panel of immunohistochemical stains was performed (S100, CD56, NB84, CD99 [MIC2], Bcl-2, CD117, CD34, desmin, MNF116, and WT1). In the 370 sections from 37 cases, all primitive neuroectodermal tumors, with and without the presence of t(11;22), demonstrated uniform membranous membrane staining with CD99 (MIC2) and focal staining with CD56, NB84, MNF116, and WT1. All rhabdomyosarcomas, both alveolar and embryonal, demonstrated uniform desmin, CD56, and cytoplasmic WT1 immunostaining. Desmoplastic small round cell tumors showed positive cytokeratin staining, with half having "dot-like" cytoplasmic desmin and WT1 positivity; some showed focal positivity for NB84, CD99, and Bcl-2. The "undifferentiated" sarcomas showed the widest range of staining, with no marker staining all cases. Neuroblastomas exhibited uniform strong staining for CD56 and NB84 and marked cytoplasmic Bcl-2 positivity, and some cases showed cytoplasmic WT1 expression. Blastematous Wilms' tumors showed uniform strong membranous staining for CD56, uniform cytoplasmic staining for Bcl-2, and nuclear expression of WT1. Embryonal pediatric malignancies can demonstrate apparently nonspecific expression patterns for several antigens, which may reflect developmental immaturity rather than specific differentiation pathways.

BackgroundPatients with chronic granulomatous disease (CGD) may have gastrointestinal manifestations, commonly colitis. The etiology, prevalence, and inflammatory process of CGD colitis are unclear. ObjectivesTo characterize the inflammatory process of CGD colitis and to compare it with other inflammatory bowel disorders. MethodsColonic mucosal biopsies from 8 CGD patients were immunostained for eosinophils, neutrophils, macrophages, and adhesion molecules (ICAM; VCAM, E-selectin) and compared with normal and diseased controls (allergic colitis, ulcerative colitis, and melanosis coli). Cell types were counted and expressed as cell/mm2 ResultsThe inflammatory infiltrate in CGD colitis differed from the normal controls by an increase in eosinophils (110; 48–176 [median and range] versus 14.5; 3–30;P < 0.005) and macrophages (291.5; 203–480 versus 38.5; 27–64;P < 0.005). There was a paucity of neutrophils compared to ulcerative colitis (10; 0–101 versus 315.5; 78–688;P < 0.005). Expression of HLA-DR was increased in the epithelium and vascular endothelium in CGD compared with normal controls. Patterns of expression of the adhesion molecules differed significantly in CGD from those in other inflammatory bowel diseases: intracellular adhesion molecule-1 was more strongly expressed in the lamina propria, vascular adhesion molecule-1 was more patchily expressed, and E-selectin was present only in the small vessels. ConclusionsThe mechanism of inflammation and profile of inflammatory mediators in CGD colitis differs from that in other inflammatory bowel diseases.

Concordance for neuroblastoma in monozygotic twins has been reported only rarely, and the cause of the shared pathology has not been established. We describe a case of infant monozygotic twins developing tumours that were morphologically, clinically and molecularly indistinguishable, but with a delay of 6 months between times of presentation. Both tumours were metastatic and had amplification of MYCN and deletion at 1p36. Twin 1, who developed neuroblastoma first, had constitutional karyotype abnormalities in at least 5% of peripheral blood mononuclear cells involving 1p and 3p, and a deletion of 1q44 in 21% of cells. Twin 2 had a normal constitutional karyotype and lacked rearrangement or deletion of these regions. We propose an acquired neuroblastoma predisposition specific for twin 1, and in utero metastatic spread of tumour cells to twin 2 via the shared placental circulation. © 2001 Cancer Research Campaign http://www.bjcancer.com

The article by Sheriff et al on the use of paraffin wax embedded muscle for the diagnosis of muscular dystrophy1 illustrates some valid points, but some are questionable. Excellent results are illustrated and some retrospective studies of archival material will clearly be possible. However, many of us in the field of muscle pathology will be alarmed at the statement in the discussion that “ . . .frozen muscle tissue is no longer necessary for the diagnosis of muscular dystrophy, with the exception of LGMD2F”. This statement is premature, inaccurate, and only deals with a limited number of muscular dystrophies. It also takes no account of the fact that the type of neuromuscular disorder is not known before a biopsy is taken, so tissue must be prepared for all possible studies. Enzyme histochemistry still has an important role, and requires frozen tissue.2 The authors take no account of the importance of immunoblotting, which …

We thank Drs. Sebire and colleagues for presenting their data that corroborates our recently reported findings [1]. Their four new cases bring the total number of reports on cytogenetic findings in pleuropulmonary blastoma (PPB) to 14. Twelve of the 14 cases have shown relative excesses in material from chromosome 8. The remaining two cases have shown gains in chromosome 8 that, in the setting of other numerical abnormalities, may not represent relative gains. We too are beginning to feel that cytogenetic analysis may play a useful role in the interpretation of certain diagnostically difficult childhood thoracic neoplasms. Within the last month, we applied the technique to an unusual case of a 4-year-old boy whose medical records had been lost at a hospital in Haiti. He presented with a tumor replacing the left hemithorax. He had a healed abdominal midline incision and a radiologically absent kidney. The mother stated that a mass had been removed at the age of 2. Needle biopsies of the thoracic mass showed tumor cells with an embryonal pattern of rhabdomyoblastic differentiation; epithelium, suspected to represent underlying lung, was also present. The histologic differential diagnosis included metastatic Wilms tumor with prominent rhabdomyoblastic differentiation, rhabdomyosarcoma metastatic from an abdominal primary, or PPB. Karyotype was 73763n,XXY,

Aim—At present, the diagnosis of muscular dystrophy is made by means of immunohistochemistry on frozen sections. The aim of this study was to develop a sensitive and reproducible immunohistochemical method for use on formalin fixed, paraffin wax embedded sections for the demonstration of dystrophin associated proteins and other muscle associated antigens. Methods—All the cases studied were from the files of the department of histopathology, Great Ormond Street Hospital for Children NHS Trust. Immunohistochemistry was performed on paraffin wax embedded sections with heat mediated antigen retrieval and overnight incubation with the antibodies at room temperature. Four different pretreatment buffers were tested in the attempt to optimise the immunostaining. Frozen sections were run in parallel for direct comparison. Results—All the antibodies except δ sarcoglycan gave strong, consistent immunostaining in paraffin wax embedded sections, comparable with the frozen sections. The most consistent results were obtained using citrate/EDTA as the pretreatment buffer. Conclusion—A reliable and reproducible technique has been established, using a heat mediated citrate/EDTA buffer antigen retrieval method, which works well for most of the antibodies needed to make the diagnosis of muscular dystrophy in formalin fixed, paraffin wax embedded sections. This technique overcomes some of the inherent problems encountered using frozen muscle tissue and it could become a valuable tool for the diagnosis of muscular dystrophy.