Paraneoplastic pemphigus and Castleman's disease: a case report and a revision of the literature.

BACKGROUND: In literature, a few reports described an association between paraneoplastic pemphigus (PNP) and Castelman's disease (CD), but no consensus have been proposed for the diagnostic-therapeutical approach. Aim of this study is to present a case report and explore the relationship between PNP and CD in pediatric patients, focusing on clinical manifestations, histopathological findings, treatment and outcome to find elements for an early diagnosis. CASE PRESENTATION: We present the clinical case of a 13 years old girl with a challenging diagnosis of PNP and CD who underwent therapy at first with Rituximab and then with Siltuximab, for the control of symptoms. CONCLUSIONS: Reviewing literature, 20 clinical cases have been described in the pediatric age. Diagnosis may be challenging, requiring an average of 3 months (range from 3 weeks to 2 years). In all cases, the initial manifestations were mucocutaneous lesions, especially oral lesions with poor response to conventional treatment. Systemic symptoms may be present as well. Therapeutical approach is still discussed with no consensus. Almost all patients received corticosteroids with poor response. Other drugs including azathioprine, methotrexate, cyclosporine and monoclonal antibodies have been evaluated for the control of the disease. Further studies and experimental trials urge to define the diagnostic criteria and therapy protocol.

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott-Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients' cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions.

Expanding phenotype of FAM111B-related disease focusing on liver involvement: Literature review, report of a case with end-stage liver disease and proposal for a new acronym.

POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review focusing on the frequency and the impact of hepatic involvement and a case report of a patient with severe end-stage liver disease. Whole exome sequencing (WES) was conducted on the proband and his parents. A de novo FAM111B: c.1879A > G; (p.Arg627Gly) variant was identified. Hepatic involvement is present in 11 out of the 30 patients described in the literature, with different levels of dysfunction ranging from mild transaminitis to liver fibrosis found in three different cases by liver biopsies. Liver involvement seems to be a significant cause of morbidity. We propose to modify the previous acronym in POIK-TMPL: including POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis/pancreas insufficiency and cancer, liver involvement/lymphedema. Moreover, we suggest screening patients with FAM111B variants for liver involvement from the first month of life and continue with an appropriate follow-up. Further studies are needed to better understand this frequent complication.

Epidermolysis Bullosa in children: the central role of the pediatrician.

Epidermolysis bullosa (EB) is a severe hereditary disease characterized by defective epithelial adhesion causing mucocutaneous fragility. The major types are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and more than 35 EB subtypes. Another very rare type of EB is Kindler EB (KEB). Clinically, it is a very heterogeneous disease which ranges from localized to extensive skin lesions with frequent multisystem extra cutaneous involvement. The role of a pediatrician-dermatologist cooperation within a multidisciplinary team is fundamental for both the diagnosis and management contributing to these patients' better life expectancy. Aim of this study is to describe clinical and laboratory characteristics of the main EB subtypes focusing on nutritional and gastrointestinal aspects, providing information to aid the paediatric management of children with EB. This retrospective study reviewed the cases of 160 pediatric EB patients (76 male and 84 female): 31 patients affected by EBS (mean age ± SD: 4.37 ± 7.14), 21 patients affected by JEB (mean age ± SD: 9.26± 17.30) and 108 with DEB (mean age ± SD: 11.61 ± 13.48). All patients were admitted at the Bambino Gesù Children's Hospital in Rome, between June 2005 to June 2020. The reduced gastrointestinal absorption, chronic losses, esophageal stenosis and chronic inflammatory state, represent the basis of nutritional problems of EB patients. In particular, anemia represents one of the most important complications of DEB patients which could require transfusion-dependent patterns. Malnutrition, vitamin deficiencies and anemia have been related to growth delay in EB patients. A specific diet with a balance of all macronutrients is required and improving caloric intake with sugar limitations is fundamental to prevent dental caries and tooth decay typical of EB patients. While sepsis proved to be the major cause of morbidity and mortality in younger patients, squamous cell carcinoma was mostly observed in older patients, especially those affected by DEB. Patients with EB require regular monitoring for complications and sequelae with a frequency of evaluations which varies based on age and EB subtypes. Cooperation among medical teams involving paediatricians, dermatologists, specialist clinicians including nutritionists such as families and patient's association is fundamental to approach the disease and improve the quality of life of these patients.

Multidisciplinary care for patients with epidermolysis bullosa from birth to adolescence: experience of one Italian reference center.

BACKGROUND: Epidermolysis bullosa (EB) is a disabling and chronic genodermatosis characterized by mucocutaneous fragility with blister formation after minimal trauma. Severity ranges between very mild forms to extremely severe or lethal subtypes. Depending on disease subtypes, blisters may be localized also in larynx, bladder, esophagus, and most frequent disease complications are malnutrition, chronic anemia, osteoporosis, limb contracture and early development of squamous cell carcinomas. EB is classified into four major groups: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB (KEB). No specific treatment is available; however, a multidisciplinary management is mandatory in order to treat the lesions, to prevent complication, and to give a psychological support to the patient and family members. OBJECTIVE: To report the experience on a therapeutic education plan of an Italian reference center for epidermolysis bullosa in the last 30 years. METHODS: In our study we included all patients with EB from 1990 to the present, dividing them into three age groups (< 5 years, > 5-12 years and > 12-18 years). The therapeutic plan involved all multidisciplinary team members, since born until adolescence. The multidisciplinary team has been progressively established; the dermatologists act as patient case manager, in collaboration with the pediatrician, endocrinologist, dietician, dentist, plastic surgeon, digestive surgeon, geneticist, psychologist and a dedicated nurse. Other dedicated specialists are involved upon patient needs. RESULTS: Two hundred fifteen patients have been recruited and followed in our hospital since 1990. One hundred forty patients (65%) are on follow-up, 27 patients (13%) died and only 11 (5%) were lost to follow-up. Our patients manifested the specific complications related to their EB subtype in keeping with the data reported in the literature. Eighteen (8%) patients affected with JEB severe died within the first year of life, 9 patients (5%) died for squamous cell carcinoma in adulthood and were affected with recessive DEB; only 1 patient died for squamous cell carcinoma at the age of 16. CONCLUSIONS: An adequate management of EB patients require a multidisciplinary approach with an educational plan to guarantee an appropriate treatment and to support and accompany patients and their families since birth along life. The dynamic educational plan adopted in our hospital showed good clinical and psychological outcome in our population, allowing adherence to treatment, reducing the frequency of complications and improving life expectancy and quality of life.

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies.

OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Successful topical treatment of anal giant condylomata acuminata in an infant.

Anogenital condylomata acuminata are induced by human papillomavirus (HPV) and they rarely manifest in immunocompetent children. Therapeutic options depend on patient's age and general conditions and extension of the lesions. However, management is still a challenge and recurrences are frequent. Cryotherapy, laser, and surgical treatments in children are painful and frequently require general anesthesia. Imiquimod is a topical immune response modifier and constitutes a noninvasive alternative for the treatment of anogenital condylomata acuminata. Here, we report an infant admitted to our hospital with a giant vegetative papillomatous lesion on the perianal region surrounded by small satellites papules. PCR for HPV confirmed the clinical diagnosis of giant condylomata acuminata due to HPV type 6. The child has been successfully treated with topical 5% imiquimod cream without side effects. Although topical imiquimod is not licensed for pediatric age, this report highlights the potential benefits of its use in selected pediatric cases.

The Infantile Hemangioma Referral Score: A Validated Tool for Physicians.

OBJECTIVES: Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians. METHODS: In this multicenter, cross-sectional, observational study, we used a 3-stage process: (1) development of the Infantile Hemangioma Referral Score (IHReS) tool by IH experts who selected a representative set of 42 IH cases comprising images and a short clinical history, (2) definition of the gold standard for the 42 cases by a second independent committee of IH experts, and (3) IHReS validation by nonexpert primary physicians using the 42 gold standard cases. RESULTS: A total of 60 primary physicians from 7 different countries evaluated the 42 gold standard cases (without reference to the IHReS tool); 45 primary physicians evaluated these cases using the IHReS questionnaire, and 44 completed retesting using the instrument. IHReS had a sensitivity of 96.9% (95% confidence interval 96.1%-97.8%) and a specificity of 55.0% (95% confidence interval 51.0%-59.0%). The positive predictive value and negative predictive value were 40.5% and 98.3%, respectively. Validation by experts and primary physicians revealed substantial agreement for interrater reliability and intrarater repeatability. CONCLUSIONS: IHReS, a 2-part algorithm with a total of 12 questions, is an easy-to-use tool for primary physicians for the purpose of facilitating correct and timely referral of patients with IH. IHReS may help practitioners in their decision to refer patients to expert centers.

Unusual Father-to-Daughter Transmission of Incontinentia Pigmenti Due to Mosaicism in IP Males.

Incontinentia pigmenti (IP; Online Mendelian Inheritance in Man catalog #308300) is an X-linked dominant ectodermal disorder caused by mutations of the inhibitor of κ polypeptide gene enchancer in B cells, kinase γ (IKBKG)/ nuclear factor κB, essential modulator (NEMO) gene. Hemizygous IKBKG/NEMO loss-of-function (LoF) mutations are lethal in males, thus patients are female, and the disease is always transmitted from an IP-affected mother to her daughter. We present 2 families with father-to-daughter transmission of IP and provide for the first time molecular evidence that the combination of somatic and germ-line mosaicism for IKBKG/NEMO loss of function mutations in IP males resulted in the transmission of the disease to a female child. We searched for the IKBKG/NEMO mutant allele in blood, urine, skin, and sperm DNA and found that the 2 fathers were somatic and germ-line mosaics for the p.Gln132×mutation or the exon 4-10 deletion of IKBKG/NEMO, respectively. The highest level of IKBKG/NEMO mutant cells was detected in the sperm, which might explain the recurrence of the disease. We therefore recommend careful clinical evaluation in IP male cases and the genetic investigation in sperm DNA to ensure correct genetic counseling and prevent the risk of paternal transmission of IP.

Safety and effectiveness of oral propranolol for infantile hemangiomas started before 5 weeks and after 5 months of age: an Italian multicenter experience.

BACKGROUND: Despite not being licensed for the treatment of infantile hemangiomas (IH) in infants younger than 5 weeks or older than 5 months, propranolol is often used in these age groups to prevent or to treat potentially severe complications. The objective of the present study was to review the experience of 8 Italian pediatric and dermatologic centers regarding propranolol treatment for IH started before 5 weeks or after 5 months of age. METHODS: We retrospectively reviewed the records of patients followed up for IH, on propranolol treatment started before 5 weeks or after 5 months of age, and collected information on sociodemographic data, treatment indications, IH involution, IH relapse, and treatment side effects. RESULTS: A total of 343 patients were enrolled; 15 were started on propranolol before 5 weeks (group 1), 328 were started after 5 months of age (group 2). The most frequent indications were permanent aesthetical disfigurement (91.8%) and function threatening complications (42.6%). In most cases, the treatment was effective. The involution was partial in 67.7% of patients. In 11.8% of cases a relapse was observed. No relapse was observed in group 1. Treatment complications were reported in 15.8% of children, most frequently sleep disorders (6.6%), followed by irritability (5.1%) and diarrhea (2.2%). Only a case of mild constipation was observed in group 1. CONCLUSION: The safety and effectiveness profile of propranolol in infants younger than 5 weeks or older than 5 months may be acceptable. Taking in account propranolol's potential in preventing severe complications, further studies should assess the acceptability of propranolol treatment, especially in the <5-week age group .

Frequent Occurrence of Aplasia Cutis Congenita in Bullous Dermolysis of the Newborn.

Bullous dermolysis of the newborn (BDN) is a subtype of dystrophic epidermolysis bullosa characterized by rapid improvement in skin fragility within the first months of life, associated with typical immunofluorescence and ultrastructural features. Inheritance can be autosomal dominant or recessive. We report here 4 cases of BDN, 2 of which presented with aplasia cutis congenita of the lower extremities. All patients improved rapidly and blister formation ceased by the third month of life in 3 cases. In these patients only residual milia, nail dystrophies and atrophic scarring at sites of aplasia cutis were visible by one year. Family history indicated dominant inheritance in 2 cases, confirmed by identification of COL7A1 mutation. Molecular analysis also revealed recessive inheritance in the 2 sporadic cases. A literature search identified several patients with BDN born with skin defects localized to the lower extremities. In conclusion, these findings indicate that aplasia cutis congenita is not an infrequent manifestation of BDN.

Treatment of infantile haemangiomas: recommendations of a European expert group.

UNLABELLED: With a prevalence of 2.6-4.5 %, infantile haemangiomas (IH) represent the most common tumour of infancy. While the majority of IH does not require therapy and regresses spontaneously, about 10 % of IH exhibit complications such as obstruction, ulceration or disfigurement. With the advent of oral propranolol, many conventional treatment options have become obsolete. This paper summarizes current recommendations for management of complicated IH. These recommendations have been written by an expert group after a consensus process including bibliographic review, several drafts of synthesis, meetings with quantitative voting system and redaction of an approved final manuscript. CONCLUSION: Oral propranolol is the first-line agent for the treatment of complicated IH. WHAT IS KNOWN: • Infantile haemangiomas (IH) are the most common tumours of infancy. Within a very short period after its discovery and long before the publication of randomized controlled trials, propranolol has become the number one agent for the treatment of complicated IH. What is New: • We report IH treatment recommendations of an international, interdisciplinary team of experts, based on an up-to-date review of the literature.

Buschke-Ollendorff syndrome: sparing unnecessary investigations.

Buschke-Ollendorff syndrome (BOS) is an autosomal-dominant disease characterized by the association of connective tissue nevi and osteopoikilosis. It is diagnosed by mutations of proteins involved in bone and connective tissue morphogenesis. We report 2 cases of BOS with different cutaneous clinical patterns. These cases emphasize the importance of heightened suspicion of BOS in selected cases. Identifying BOS can be reassuring for the patient, sparing futile and expensive investigations.

Preemptive liver transplantation in a child with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL-cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life-long recurrent apheresis to reduce plasma LDL-cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5-yr-old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low-fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL-cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications.

Vesiculopustular eruption in a neonate with trisomy 21 syndrome as a clue of transient myeloproliferative disorders.

We report the case of a vesiculopustular eruption associated with a transient myeloproliferative disorder (TMD) in a neonate with trisomy 21 syndrome. Examination of a skin biopsy showed a dermal mixed inflammatory infiltrate including atypical megakaryoblasts. As the white blood cell count spontaneously normalized, the eruption disappeared. This case report and review of the literature demonstrates that a vesiculopustular eruption could be an important clue to identify TMD in a neonate.

Congenital lupus erythematosus: case report and review of the literature.

Congenital presentation of neonatal lupus erythematous is very rare. We describe an infant who had congenital neonatal lupus erythematosus with atrophic lesions on the face and scarring lesions on the trunk. All radiologic, virologic, and hematologic assays were normal. Skin biopsy specimen and immunofluorescence findings led us to suspect neonatal lupus, a diagnosis confirmed by positivity for anti-Sjörgen syndrome and antinuclear antibodies both in the child and her mother. In this infant, skin manifestations represented the stable and irreversible outcome of an inflammatory stage that occurred during pregnancy.