A case report of a blueberry muffin baby caused by congenital self-healing indeterminate cell histiocytosis.

BACKGROUND: Blueberry muffin is a descriptive term for a neonate with multiple purpuric skin lesions. Many causes are known, amongst them life-threatening diseases like congenital infections or leukemia. Indeterminate cell histiocytosis (ICH) is an exceptionally rare cause of blueberry muffin rash. ICH is a histiocytic disorder which can be limited to the skin or can present with systemic involvement. A mutation that has been described in histiocytic disorders is a MAP2K1 mutation. In ICH, this mutation has previously been described in merely one case. CASE PRESENTATION: A term male neonate was admitted to the neonatology ward directly after birth because of a blueberry muffin rash. ICH was diagnosed on skin biopsy. The lesions resolved spontaneously. The patient is currently 3 years old and has had no cutaneous lesions or systemic involvement so far. This disease course is similar to that of the Hashimoto-Pritzker variant of LCH. CONCLUSIONS: ICH can manifest in neonates as resolving skin lesions. It is limited to the skin in most cases, but systemic development is possible. Therefore, it is essential to confirm the diagnosis with a biopsy before the lesions resolve and to monitor these patients closely with routine follow-up.

Acral peeling in Nagashima type palmo-plantar keratosis patients reveals the role of serine protease inhibitor B 7 in keratinocyte adhesion.

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.

Congenital Unilesional Cutaneous Langerhans Cell Histiocytosis: A Case Report.

ABSTRACT: Langerhans cell histiocytosis (LCH) is a clonal proliferation of bone-marrow-derived cells, which normally reside as epidermal and mucosal dendritic cells involved in antigen presentation. It is a rare disease more common in children than adults, that is believed to be neoplastic in most cases. The diagnosis is based on clinical and radiological findings in combination with histopathologic, immunophenotypic, or ultrastructural analyses. LCH have a broad spectrum of clinical manifestations, ranging from benign cutaneous lesions to malignant multisystem disease. Based on the extent of involvement at diagnosis, LCH can be divided in single-system LCH when only one organ or system is involved, usually with multiple lesions, and multisystem LCH, when 2 or more organs or systems are involved at diagnosis. One variant of LCH is characterized by congenital isolated cutaneous involvement. It typically manifests at birth or in the postnatal period with a widespread eruption of red-to-brown papulo-nodules or, more uncommonly, a solitary lesion. The overall prognosis for single lesion skin limited LCH is excellent and most lesions spontaneously resolve within 4-18 weeks. Systemic involvement is rare. Skin findings cannot predict systemic disease and obtaining an oncology consultation is recommended for further evaluation. Herein, we present an additional case in a full-term, well-appearing, female infant with an isolated, asymptomatic, ulcerated, papule of the left arm, that was noted at birth.

Acral peeling skin syndrome resulting from a novel homozygous mutation in the CSTA gene-A report of two cases.

Acral peeling skin syndrome is a rare genodermatosis characterized by asymptomatic peeling of the acral skin. It is usually caused by biallelic mutations in the gene TGM5. However, biallelic mutations in the CSTA gene have also been described to cause APSS with exfoliative ichthyosis, so far in only five pedigrees. Here, we report two new pedigrees, each with one patient having APSS, due to a novel CSTA mutation.

Congenital Disseminated Pyogenic Granuloma: Characterization of an Aggressive Multisystemic Disorder.

OBJECTIVE: To describe the clinical, radiologic, and histopathologic features of "congenital disseminated pyogenic granuloma" involving various organs with high morbidity related to cerebral hemorrhagic involvement. STUDY DESIGN: We searched the database of the Vascular Anomalies Center at Boston Children's Hospital from 1999 to 2019 for patients diagnosed as having multiple vascular lesions, visceral vascular tumors, congenital hemangiomatosis, multiple pyogenic granulomas, or multiple vascular lesions without a definite diagnosis. A retrospective review of the medical records, photographs, histopathologic, and imaging studies was performed. Only patients with imaging studies and histopathologic diagnosis of pyogenic granuloma were included. RESULTS: Eight children (5 male, 3 female) had congenital multifocal cutaneous vascular tumors. Lesions also were found in the brain (n = 7), liver (n = 4), spleen (n = 3), muscles (n = 4), bone (n = 3), retroperitoneum (n = 3), and intestine/mesentery (n = 2). Less commonly affected were the spinal cord, lungs, kidneys, pancreas, and adrenal gland (n = 1 each). The mean follow-up period was 21.8 months. The cerebral and visceral lesions were hemorrhagic with severe neurologic sequelae. The histopathologic diagnosis was pyogenic granuloma with prominent areas of hemorrhage and necrosis. The endothelial cells had enlarged nuclei, pale cytoplasm and were immunopositive for CD31 and negative for D2-40 and glucose transporter 1. CONCLUSIONS: Congenital disseminated pyogenic granuloma is a distinct multisystemic aggressive disorder that primarily affects the skin, brain, visceral organs, and musculoskeletal system. Differentiation of this entity from other multiple cutaneous vascular lesions is critical because of possible cerebral hemorrhagic involvement.

Intrauterine big toenail imprints: A new cause of congenital skin dimples.

Congenital skin dimples (SD) are small cutaneous depressions that can be noted on any part of the body and may be caused by traumatic, mechanical, metabolic, and genetic factors as well as by exposure to infections or drugs. We describe 3 cases of unrelated healthy newborns displaying SD and discuss as a possible explanation the persistent friction of the big toenail onto the immature skin of the fetus during intrauterine life causing as depression in the skin.

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds.

The role of epidermal proteolysis in overdesquamation was revealed in Netherton syndrome, a rare ichthyosis due to genetic deficiency of the LEKTI inhibitor of serine proteases. Recently, we developed activography, a new histochemical method, to spatially localize and semiquantitatively assess proteolytic activities using activity-based probes. Activography provides specificity and versatility compared to in situ zymography, the only available method to determine enzymatic activities in tissue biopsies. Here, activography was validated in skin biopsies obtained from an array of distinct disorders and compared with in situ zymography. Activography provides a methodological advancement due to its simplicity and specificity and can be readily adapted as a routine diagnostic assay. Interestingly, the levels of epidermal proteolysis correlated with the degree of desquamation independent of skin pathology. Thus, deregulated epidermal proteolysis likely represents a universal mechanism underlying aberrant desquamation.

Congenital self-healing reticulohistiocytosis with BRAF V600E mutation in an infant.

Congenital self-healing reticulohistiocytosis (CSHR) is a rare disorder characterized by benign skin lesions with a tendency to self-heal. Multiple skin lesions are usually present in CSHR. It is very difficult to distinguish between CSHR and an invasive Langerhans cell histiocytosis. We present a case of a 5-month-old infant girl who had hypopigmented skin lesions distributed over her neck, thorax and torso. The skin lesions regressed spontaneously 2 months after the diagnosis of CSHR and the child has remained in complete remission without any sign of recurrence over a 2-year follow-up. BRAF V600E mutation was detected in lesional cells along with a low Ki-67 proliferative activity of about 6%. BRAF oncogene-induced senescence might contribute to a mechanism of self-regression in CSHR; however, the exact role of the somatic BRAF V600E mutation in CSHR remains to be determined.

Medallion-like dermal dendrocyte hamartoma: A rare congenital CD34-positive dermal lesion clinically and pathologically overlapping with fibroblastic connective tissue nevus.

Both medallion-like dermal dendrocyte hamartoma and fibroblastic connective tissue nevus are rare benign dermal lesions composed of CD34-positive spindle cells. Although regarded as different diseases, it is sometimes difficult to distinguish between them due to their clinical and pathological similarities. We present a case of medallion-like dermal dendrocyte hamartoma that could also be diagnosed as fibroblastic connective tissue nevus and propose the possibility of overlap in these diseases.

A neonatal pustule:Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare, clinically heterogeneous disease that most commonly occurs in pediatric populations. Congenital self-limited LCH is a benign variant of LCH. It most commonly presents as a diffuse eruption and reports of single lesion cases are infrequent in the literature. Even in the case of congenital self-limited LCH, there is potential for future multisystem relapse, making long-term follow-up important. We present a case of single lesion self-limited LCH in a full-term male infant with interesting morphology. Physical examination revealed a painless, 6 millimeter, well-demarcated, papule encircled by erythema with central hemorrhage. An infectious workup was negative and a punch biopsy was obtained, which showed a dermal infiltrate of histiocytes consistent with a diagnosis of LCH. The lesion healed without intervention within three weeks. Our case highlights the need for dermatologists to consider LCH in the differential diagnosis for lesions of varying morphology in children, as proper identification is necessary to monitor for multisystem recurrence.

Connexin channels in congenital skin disorders.

Gap junctions and hemichannels comprised of connexins influence epidermal proliferation and differentiation. Significant advances in our understanding of the functional role of connexins in the skin have been made by studying the diseases caused by connexin mutations. Eleven clinically defined cutaneous disorders with an overlapping spectrum of phenotypes are caused by mutations in five different connexin genes, highlighting that disease presentation must be deciphered with an understanding of how connexin functions are affected. Increasing evidence suggests that the skin diseases produced by connexin mutations result from dominant gains of function. In palmoplantar keratoderma with deafness, the connexin 26 mutations transdominantly alter the function of wild-type connexin 43 and create leaky heteromeric hemichannels. In keratitis-ichthyosis-deafness syndrome, different connexin 26 mutations can either form dominant hemichannels with altered calcium regulation or increased calcium permeability, leading to clinical subtypes of this syndrome. It is only with detailed understanding of these subtle functional differences that we can hope to create successful pathophysiology driven therapies for the connexin skin disorders.

Case of Congenital Self-Healing Reticulohistiocytosis Expanding the Spectrum of Blueberry Muffin Baby.

Congenital self-healing reticulohistiocytosis (CSHRH) is a benign, rare variant of histiocytosis. This condition can present phenotypically as blueberry muffin baby. This is the case of a male neonate with skin involvement of papulonodular violaceous lesions, which resolved spontaneously. The diagnosis of CSHRH is confirmed using histopathology and immunohistochemistry.

Content Validity of Patient-Reported Outcome Instruments used with Pediatric Patients with Facial Differences: A Systematic Review.

OBJECTIVE: The aim of this systematic review was to identify patient-reported outcome (PRO) instruments used in research with children/youth with conditions associated with facial differences to identify the health concepts measured. DESIGN: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from 2004 to 2016 to identify PRO instruments used in acne vulgaris, birthmarks, burns, ear anomalies, facial asymmetries, and facial paralysis patients. We performed a content analysis whereby the items were coded to identify concepts and categorized as positive or negative content or phrasing. RESULTS: A total of 7,835 articles were screened; 6 generic and 11 condition-specific PRO instruments were used in 96 publications. Condition-specific instruments were for acne (four), oral health (two), dermatology (one), facial asymmetries (two), microtia (one), and burns (one). The PRO instruments provided 554 items (295 generic; 259 condition specific) that were sorted into 4 domains, 11 subdomains, and 91 health concepts. The most common domain was psychological (n = 224 items). Of the identified items, 76% had negative content or phrasing (e.g., "Because of the way my face looks I wish I had never been born"). Given the small number of items measuring facial appearance (n = 19) and function (n = 22), the PRO instruments reviewed lacked content validity for patients whose condition impacted facial function and/or appearance. CONCLUSIONS: Treatments can change facial appearance and function. This review draws attention to a problem with content validity in existing PRO instruments. Our team is now developing a new PRO instrument called FACE-Q Kids to address this problem.

Dermatologic surgery in children: an update on indication, anesthesia, analgesia and potential perioperative complications.

BACKGROUND: Children undergoing dermatosurgical procedures require, unlike adults, particular attention; the administration of various analgesics, anesthetics or sedatives requires a thorough knowledge of drug pharmacokinetics and pharmacodynamics. Furthermore, there are concerns that drugs used for sedation/general anesthesia may result in anesthetic/analgesic complications in children undergoing surgery, with a risk of impaired mental development. OBJECTIVES: Based on our clinical experience and a literature review, we illustrate the most commonly used analgesic, anesthetic and sedative drugs in pediatric dermatosurgery, and identify risk factors and complications following dermatosurgical procedures. RESULTS: Topical anesthetics can be used in children for superficial dermatologic procedures or prior to infiltration anesthesia. Maximum recommended doses based on body weight should be calculated in order to avoid overdosage of local anesthetics. General anesthesia in dermatosurgery is considered safe and has a low rate of side effects. However, caution is advised in children under the age of one due to potential long-term neurological side-effects. NSAIDs and opioids play a significant role in analgesia for children. CONCLUSIONS: This article reviews currently available data on analgesia, anesthesia and complications that may arise in pediatric dermatosurgery. These data may be useful in optimizing the safety and quality of care and in improving parent counseling.

Medical Mimics of Child Abuse.

OBJECTIVE: Physicians have an ethical and legal mandate to identify abused children so that they may be protected from further harm and are simultaneously required to think broadly and objectively about differential diagnoses. The medical literature is replete with examples of medical diseases that mimic abuse, potentially leading to misdiagnoses and subsequent harm to children and families. CONCLUSION: This review highlights some of the common and uncommon diseases that mimic physical and sexual abuse of children.

Congenital neurocristic cutaneous hamartoma with poliosis: A case report.

Neurocristic cutaneous hamartomas (NCH) are rare, pigmented skin lesions derived from the abnormal migration of neural crest cells. We report the case of a 57-year-old female with a congenital localized area of poliosis and underlying pigmented patch on her scalp. Analysis of 2 punch biopsies yielded features consistent with NCH. Histopathology revealed schwannian-differentiated spindle cells and melanocytic components in the dermis. The spindle cells stained positively for S-100 and the stroma showed a prominent CD34 staining. The melanocytes were positive for melanoma triple stain (HMB-45, Melan A, Tyrosinase) and S-100. As the presentation of NCH and focal poliosis has yet to be described, we will present a literature review of NCH and discuss common features and associations of poliosis.

Acral peeling skin syndrome associated with a novel CSTA gene mutation.

Acral peeling skin syndrome (APSS) is a rare autosomal recessive condition, characterized by asymptomatic peeling of the skin of the hands and feet, often linked to mutations in the gene TGM5. However, more recently recessive loss of function mutations in CSTA, encoding cystatin A, have been linked with APSS and exfoliative ichthyosis. We describe the clinical features in two sisters with APSS, associated with a novel large homozygous deletion encompassing exon 1 of CSTA.