Clinical and radiological improvement in Gorham-Stout disease after sirolimus treatment.

BACKGROUND: Gorham-Stout disease (GSD) is a rare syndrome characterized by lymphatic malformations, mainly in bone structures, causing progressive osteolysis. Lymphatic endothelial cell proliferation depends on several growth factors that use the phosphoinositide-3 kinase (PI3K)/Akt pathway and converge on the mammalian target molecule of the rapamycin (mTOR) pathway. These findings have allowed treating GSD with mTOR pathway inhibitors such as sirolimus or everolimus. CASE REPORT: We present the case of a one-year-old female patient referred to our institution after a right femur fracture and progressive limb volume increase, disproportionately to the trauma. After several episodes of soft tissue infections, imaging studies showed pseudarthrosis, lytic lesions, and progressive loss of the right femur that ended in total absence. A femur biopsy showed lymphatic structures positive with D2-40 staining, diagnosing GSD. After six months of non-response to traditional treatments, the limb was disarticulated at the hip level, and oral sirolimus treatment was initiated, showing clinical and radiological improvement with minor lytic lesions and evidence of ossification after 20 months of treatment. CONCLUSIONS: Oral sirolimus treatment for GSD inhibits angiogenesis and osteoclastic activity, stimulating bone anabolism and leading to arrested osteolysis progression and improved ossification, quality of life, and patient prognosis. Therefore, sirolimus should be considered a therapeutic option for this rare disease.

INTRODUCCIÓN: La enfermedad de Gorham-Stout es un trastorno poco frecuente caracterizado por malformaciones linfáticas localizadas sobre estructuras óseas que causan osteólisis progresiva. La proliferación de células endoteliales linfáticas depende de factores de crecimiento que utilizan la vía de la fosfoinositida-3 cinasa (PI3K)/Akt y convergen en la vía de la molécula diana de rapamicina de los mamíferos (mTOR). Este conocimiento ha permitido el tratamiento de esta enfermedad con inhibidores de esta vía como sirolimus o everolimus. CASO CLÍNICO: Se presenta el caso de una paciente de sexo femenino de un año referida a nuestra institución tras presentar fractura de fémur derecho y aumento de volumen de dicha extremidad posterior a un traumatismo. Después de diversos episodios de infecciones de tejidos blandos se realizaron estudios de imagen que mostraron pseudoartrosis, lesiones líticas y ausencia total del fémur derecho, así como una biopsia de fémur que mostró estructuras vasculares positivas con tinción D2-40, diagnosticándose enfermedad de Gorham-Stout. Durante su abordaje, se realizó la desarticulación de la extremidad a nivel de la cadera y se inició tratamiento con sirolimus oral, presentando una mejoría clínica y radiológica con menores lesiones líticas y evidencia de osificación posterior a 20 meses de tratamiento. CONCLUSIONES: El tratamiento con sirolimus oral para la enfermedad de Gorham-Stout inhibe la actividad osteoclástica y la angiogénesis, estimulando el anabolismo óseo que resulta en la detención de la progresión de la osteólisis y una mejoría en la osificación, la calidad de vida y el pronóstico del paciente. Por tal motivo, el sirolimus debe considerarse como una opción terapéutica para esta enfermedad.

Clinical and radiological improvement in Gorham-Stout disease after sirolimus treatment / Mejoría clínica y radiológica en la enfermedad de Gorham-Stout después del tratamiento con sirolimus

Abstract Background: Gorham-Stout disease (GSD) is a rare syndrome characterized by lymphatic malformations, mainly in bone structures, causing progressive osteolysis. Lymphatic endothelial cell proliferation depends on several growth factors that use the phosphoinositide-3 kinase (PI3K)/Akt pathway and converge on the mammalian target molecule of the rapamycin (mTOR) pathway. These findings have allowed treating GSD with mTOR pathway inhibitors such as sirolimus or everolimus. Case report: We present the case of a one-year-old female patient referred to our institution after a right femur fracture and progressive limb volume increase, disproportionately to the trauma. After several episodes of soft tissue infections, imaging studies showed pseudarthrosis, lytic lesions, and progressive loss of the right femur that ended in total absence. A femur biopsy showed lymphatic structures positive with D2-40 staining, diagnosing GSD. After six months of non-response to traditional treatments, the limb was disarticulated at the hip level, and oral sirolimus treatment was initiated, showing clinical and radiological improvement with minor lytic lesions and evidence of ossification after 20 months of treatment. Conclusions: Oral sirolimus treatment for GSD inhibits angiogenesis and osteoclastic activity, stimulating bone anabolism and leading to arrested osteolysis progression and improved ossification, quality of life, and patient prognosis. Therefore, sirolimus should be considered a therapeutic option for this rare disease.

Resumen Introducción: La enfermedad de Gorham-Stout es un trastorno poco frecuente caracterizado por malformaciones linfáticas localizadas sobre estructuras óseas que causan osteólisis progresiva. La proliferación de células endoteliales linfáticas depende de factores de crecimiento que utilizan la vía de la fosfoinositida-3 cinasa (PI3K)/Akt y convergen en la vía de la molécula diana de rapamicina de los mamíferos (mTOR). Este conocimiento ha permitido el tratamiento de esta enfermedad con inhibidores de esta vía como sirolimus o everolimus. Caso clínico: Se presenta el caso de una paciente de sexo femenino de un año referida a nuestra institución tras presentar fractura de fémur derecho y aumento de volumen de dicha extremidad posterior a un traumatismo. Después de diversos episodios de infecciones de tejidos blandos se realizaron estudios de imagen que mostraron pseudoartrosis, lesiones líticas y ausencia total del fémur derecho, así como una biopsia de fémur que mostró estructuras vasculares positivas con tinción D2-40, diagnosticándose enfermedad de Gorham-Stout. Durante su abordaje, se realizó la desarticulación de la extremidad a nivel de la cadera y se inició tratamiento con sirolimus oral, presentando una mejoría clínica y radiológica con menores lesiones líticas y evidencia de osificación posterior a 20 meses de tratamiento. Conclusiones: El tratamiento con sirolimus oral para la enfermedad de Gorham-Stout inhibe la actividad osteoclástica y la angiogénesis, estimulando el anabolismo óseo que resulta en la detención de la progresión de la osteólisis y una mejoría en la osificación, la calidad de vida y el pronóstico del paciente. Por tal motivo, el sirolimus debe considerarse como una opción terapéutica para esta enfermedad.

Concordance between referral and final diagnoses of pediatric patients with vascular malformations / Concordancia entre el diagnostico de referencia y final de pacientes pediátricos con malformaciones vasculares

Abstract Background: Vascular malformations (VaM) are a heterogeneous group of disorders resulting from the dysmorphogenesis of blood vessels. Although correct classification is relevant to providing adequate treatment according to evidence-based medicine, diagnostic terminology may be misused or need clarification. Methods: We conducted a retrospective study to measure agreement and concordance between referral and final confirmed diagnoses of 435 pediatric patients with VaM newly referred to the multidisciplinary Vascular Anomalies Clinic (VAC) using Fleiss kappa (κ) concordance analysis. Results: We found fair concordance between referral and confirmed diagnoses of VaM (κ 0.306, p < 0.001). Lymphatic malformations (LM) and VaM associated with other anomalies showed moderate diagnostic concordance (κ 0.593, p < 0.001 and κ 0.469, p < 0.001, respectively). Conclusions: Continuing medical education strategies are required to improve physician knowledge and diagnostic accuracy in patients with VaM.

Resumen Introducción: Las malformaciones vasculares (MVa) son un grupo heterogéneo de trastornos resultantes de la dismorfogénesis de los vasos sanguíneos. A pesar de que la correcta clasificación es relevante para brindar un adecuado tratamiento de acuerdo con la medicina basada en la evidencia, la terminología diagnóstica podría resultar confusa o utilizarse de manera inapropiada. Métodos: En este estudio retrospectivo se midieron el acuerdo y la concordancia entre los diagnósticos de referencia (o derivación) y los diagnósticos finales confirmados de 435 pacientes pediátricos con MVa recién remitidos a la Clínica de anomalías vasculares (CAV) multidisciplinaria, mediante el análisis de concordancia kappa de Fleiss (κ). Resultados: Se encontró una buena concordancia entre los diagnósticos de referencia (o derivación) y los diagnósticos confirmados de MVa (κ 0.306, p < 0.001). Las malformaciones linfáticas (LM) y las MVa asociadas con otras anomalías presentaron concordancias diagnósticas moderadas (κ 0.593, p < 0.001 y κ 0.469, p < 0.001, respectivamente). Conclusiones: Se requiere de estrategias de educación médica continua para mejorar el conocimiento de los médicos y la precisión diagnóstica de los pacientes con MVa.

Conradi-Hünermann-Happle syndrome: Clinical and trichoscopic findings.

Conradi-Hünermann-Happle syndrome (CHHS) is a rare genodermatosis resulting from mutations in the EBP (emopamil binding protein) gene. Dermatologic manifestations may include cicatricial alopecia, ichthyosis, follicular atrophoderma, pigmentary abnormalities, and nail dystrophy. In addition to genetic testing and clinical findings, trichoscopic findings may aid in the diagnosis. In this case report, we discuss the trichoscopic findings in a 3-year-old girl with CHHS and how these findings help us understand the pathophysiology of this disease.

Epidermolysis Bullosa Acquisita: A Rare Autoimmune Blistering Disease in Children.

A 7-year-old girl presented with a 2-year history of recurrent blisters on the skin and oral mucosa. The patient was otherwise healthy, and her family history was unremarkable for any dermatologic or other medical disease. Examination revealed multiple tense vesicles, milia, and atrophic scars present over the extensor surface of the extremities and erosions on the oral mucosa (Figure 1). A skin biopsy established a pauci-inflammatory subepidermal blister (Figure 2a). Direct immunofluorescence (DIF) evidenced the linear deposition of immunoglobulin G (IgG), immunoglobulin M (IgM), and κ and λ chains at the dermal-epithelial junction (DEJ). Indirect immunofluorescence (IIF), using the salt-split technique, established anti-epithelial antibodies on the dermal side (Figure 2b). An enzyme-linked immunosorbent assay (ELISA) was positive for Collagen Type VII (COL7) antibodies. A diagnosis of epidermolysis bullosa acquisita (EBA) was made, and treatment with azathioprine and deflazacort was administered for 8 months with progressive lessening of her symptomatology and complete clinical response at 2-year follow-up. (SKINmed. 2022;20:460-462).

Usefulness of Trichoscopy over Hair Light Microscopy in Menkes Disease.

Menkes disease (MD) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the ATP7A gene, with a high mortality rate within the first 3 years of life. It typically affects males and is characterized by impaired copper distribution and malfunction of several copper-dependent enzymes. Patients develop progressive muscle hypotonia associated with neurological damage and hair shaft dysplasia - particularly pili torti. Pili torti is usually very subtle in the first 3 months of life and gradually increases during the first year. Light microscopy examination in search for pili torti requires the observation of more than 50 hair shafts. In contrast, trichoscopy with a hand-held dermatoscope allows to easily identify the hair shaft defect. We report a case of a Hispanic male infant with MD in whom we show that trichoscopy is superior to hair light microscopy in revealing pili torti.

Bronchiolitis Obliterans With Anti-Epiplakin Antibodies in a Boy With Paraneoplastic Pemphigus.

Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by a recalcitrant and severe mucositis, and polymorphic cutaneous lesions, associated with benign and malignant neoplasms. Paraneoplastic pemphigus is caused by production of autoantibodies against various epidermal proteins involved in cell adhesion. Bronchiolitis obliterans (BO) is one of the leading causes of mortality in these patients. Recent advances have associated the presence of anti-epiplakin antibodies with the development of BO in adult patients. Here we describe the first pediatric patient in whom the association of anti-epiplakin antibodies and BO have been reported so far.

Diagnostic and therapeutic caveats in Griscelli syndrome.

Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.

Primary cutaneous blastic plasmacytoid dendritic cell neoplasm in a child: A challenging diagnosis and management.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy of the skin and hematopoietic system. There are few pediatric cases reported in the literature. Management of primary cutaneous BPDCN is challenging because, despite an apparently indolent clinical presentation, rapid dissemination with high mortality can occur. We describe a child with isolated cutaneous involvement who had a good response to chemotherapy as first-line treatment of BPDCN.

Clinical, trichoscopy, and light microscopic findings in hypohidrotic ectodermal dysplasia: Report of 21 patients and a review of the literature.

INTRODUCTION: Hypohidrotic ectodermal dysplasia (HED) is a genetic condition typified by alterations in skin structures including sweat glands, hair, nails, and teeth. Hair findings in HED have been poorly characterized in larger series. OBJECTIVE: To characterize scalp and hair findings of patients with HED clinically and with trichoscopy and light microscopy. METHODS: A cross-sectional study in 21 pediatric HED patients was performed using available clinical and scalp dermatoscopic images, as well as pulled-hair samples for clinical evaluation, trichoscopic, and light microscopic analyses. RESULTS: Seventeen out of 21 patients (81%) were men. Twenty patients had straight hair. Sixteen patients had decreased hair density, 6 of whom had hair loss mainly in the temporal and occipital regions. Fourteen patients had hair whorls. On trichoscopy, we observed: single-hair follicular units (n = 19, 90%), scalp hyperpigmentation (n = 13, 62%), variable diameter of the hair shafts (n = 12, 57%), perifollicular scales (n = 8, 38%), scalp erythema (n = 8, 38%), and short curly pigtail hairs (n = 6, 29%). On light microscopy, findings included: hair shafts with irregular diameter (n = 7, 33%), heterogeneous hair color (n = 6, 29%), trichoptilosis (n = 2, 10%), and pili torti (n = 1, 5%). CONCLUSIONS: In this series, hair findings in HED were similar to those described in previous studies. However, we describe two new clinical and two trichoscopic findings: decreased hair density mainly in the temporal and occipital regions, oblique upwards occipital hair follicles orientation, angled hairs, and short curly pigtail hairs. These heterogeneous findings may reflect the multiple factors and signaling pathways that can be affected in these syndromes.

Usefulness of the skin biopsy as a tool in the diagnosis of silvery hair syndrome.

BACKGROUND/OBJECTIVES: Silvery hair syndrome is a rare, autosomal-recessive entity characterized by silvery gray hair, eyebrows, and eyelashes and may be associated or not with immunologic or neurologic alterations. Two main types have been recognized: Chediak-Higashi syndrome and Griscelli syndrome. Hair shaft examination under light microscopy has been a useful tool to differentiate Chediak-Higashi syndrome from Griscelli syndrome, although distribution of melanin varies according to hair color related to ethnicity. The objective was to compare the pattern of melanin in the skin and with the pattern of melanin distribution in the hair shaft. METHODS: Sixteen patients with silvery hair syndrome were selected (Chediak-Higashi syndrome 5, Griscelli syndrome 11). The distribution of melanin granules in skin and hair shafts was compared and correlated with clinical diagnoses. RESULTS: Chediak-Higashi syndrome was characterized by small granules of melanin uniformly distributed throughout the thickness of the epidermis. Griscelli syndrome was characterized by an irregular pigment distribution in the epidermal basal layer with large and dense granules alternating with areas lacking melanin pigment. In two cases, study of the hair was not conclusive, but the skin showed the characteristic pattern of Griscelli syndrome. CONCLUSION: Skin biopsy is a useful tool in differentiating Chediak-Higashi syndrome from Griscelli syndrome and as a complementary study in cases in which hair shaft pigment distribution does not support the diagnosis, especially in patients with fair hair. The distribution of melanin granules in the skin correlates with that observed in the hair shaft, allowing Chediak-Higashi syndrome to be differentiated from Griscelli syndrome, at any age.

Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.

Cytogenomic and phenotypic analysis in low-level monosomy 7 mosaicism with non-supernumerary ring chromosome 7.

We present the literature review of ring chromosome 7 and clinical, cytogenetic and fine molecular mapping of the first postnatal report of a male child with a non-supernumerary ring chromosome 7, r(7). The patient had dysmorphic features, developmental delay, dermatologic lesions with variable pigmentation, hypogenitalism, lumbar dextroscoliosis, cerebellar and ophthalmological abnormalities, and melanocytic congenital nevi. Cytogenetic analysis of peripheral blood and the nevus sample showed the presence of three different cell lines r(7), monosomy 7, and duplicated r(7) (idic r(7)), while findings on fibroblasts from both light and dark skin showed only mosaicism with r(7) and monosomy 7 cell lines in various proportions. FISH assay of the ring chromosome showed subtelomeric loss in both chromosome arms in all tissues studied. Analysis by genome-wide single-nucleotide polymorphism array showed a 0.8 Mb deletion in 7p22.3 (involving eight genes) and a 7.5 Mb deletion in 7q36 (involving 29 genes including some involved in genital and central nervous system development). The combination of results from our karyotypic and array analyses enabled us to establish an accurate genotype-phenotype relationship.

Hydroa vacciniforme-like lymphoma: a chronic EBV+ lymphoproliferative disorder with risk to develop a systemic lymphoma.

Hydroa vacciniforme-like lymphoma (HVLL) is an Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder of childhood that occurs mainly in Central and South America and Asia. We present the clinicopathological features of 20 Mexican children with HVLL with a median age of 8 years at diagnosis (range, 1-15). All patients presented with skin lesions involving sun-exposed areas, but not exclusively. Fever, lymphadenopathy, and hepatosplenomegaly were often observed. Most patients were treated with immunomodulators and/or immunosuppressive agents, resulting in temporary remission. For 13 patients follow-up was available for a median of 3 years (range, 1 month-13 years). Three patients with long follow-up (9-13 years) are alive with disease. Four patients died, 2 after developing systemic lymphoma. Histologically, the skin showed a predominantly angiocentric and periadnexal Epstein-Barr early RNA+ lymphoid infiltrate with variable atypia and subcutaneous involvement. Fifteen patients showed a T-cell phenotype (12, αß; 2, γδ; 1, silent phenotype) and monoclonal T-cell receptor-γ rearrangements, whereas 6 exhibited a natural killer (NK)-cell phenotype. Four patients had hypersensitivity to mosquito bites. One patient showed both phenotypes. HVLL is an EBV-associated lymphoproliferative disorder of αß-, γδ-, or NK-cell phenotype with a broad clinical spectrum, usually prolonged clinical course, and risk for progression to systemic disease.

Dermoid cysts: a report of 75 pediatric patients.

Dermoid cysts (DCs) are benign cutaneous tumors that tend to persist and grow. The aim of this study was to examine the clinicopathologic features of congenital DCs. We present a case series of 75 children with a clinicopathologic diagnosis of DC. Seventy-two cysts were located on the head, one on the neck, and two on the trunk. Six cysts were located along the midline. Eight patients had symptoms other than changes in cyst size. Imaging studies were performed on 15 patients. Surgical excision was the primary treatment in all 75 cases. Neurosurgery and ophthalmology services were involved in the care of some patients. Histopathologic studies reported a foreign body giant cell reaction in 17 of the cysts. No recurrence was documented. DCs can remain stable for years, but they can become symptomatic as a result of enlargement and rupture or, more rarely, as a result of extension into surrounding tissues. Physicians should be aware that certain locations have a higher risk of DC extension, and adequate diagnostic investigations should be performed before their complete resection.

Neonatal vesiculopustular eruption associated with transient myeloproliferative disorder: report of four cases.

BACKGROUND: Transient myeloproliferative disorder (TMD) affects up to 10% of patients with Down syndrome (DS). A small proportion of newborns are asymptomatic and only manifest circulating blast cells, with or without leukocytosis, while others present with hepatomegaly, splenomegaly, serous effusions, and liver fibrosis. Few cases in the literature also have skin manifestations, described as crusted, erythematous, vesiculopustular eruptions occurring mainly on the face, with spreading to the trunk and extremities. MATERIALS AND METHODS: Four patients with DS and TMD were studied due to the presence of cutaneous eruptions. Systemic involvement, work-up, and follow-up were documented for each patient. Our results were compared with the previously reported cases. RESULTS: All patients were males, with ages ranging from 1 to 20 days at the time of diagnosis. In three patients, the eruption was papulopustular, and two of them also had vesicles. In one patient, lesions resembled bullous impetigo. In all, the lesions involved the face, followed by the extremities in three and the trunk in two patients. Pathergy phenomena was present in one patient. Hepatomegaly and a leukemoid reaction were present in all patients. Bone marrow showed an M7 immunophenotype in three patients and normal cellularity in one. Follow-up ranged from 2 to 11 months, during which the patients were healthy. CONCLUSIONS: Recognition of the cutaneous eruptions associated with TMD in neonate patients with DS may lead to early diagnosis and avoidance of unnecessary chemotherapy. However, because leukemia may develop later, careful follow-up is mandatory in all cases.