Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile.

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.

[Neonatal lupus erythematosus, a clinical case]. / Lupus eritematoso neonatal, caso clínico.

Neonatal lupus erythematosus (NLE) is a very rare autoimmune disease, occurring in neonates born to mothers who present auto-antibodies to cytoplasmic antigens of Sjögren's syndrome. In most cases, the clinical course is benign toward spontaneous resolution, but there is a group of patients who develop severe involvement of the cardiac conduction system, therefore, early detection is critical. OBJECTIVE: To describe a clinical case of neonatal lupus erythematosus emphasizing the importance of timely diagnosis in the patient and the mother. CLINICAL CASE: A 33-year-old woman, with a history of hypertension, came to the dermatology department for her 15-day-old male neonate who presented a recent onset of round, erythematous, raised-edged, and non-scaling plaques consistent with NLE. Cardiac conduction involvement was ruled out. Newborn's laboratory tests showed moderate neutropenia, mild increase of transaminases, and positive anti-Ro and anti-La antibodies. On directed anamnesis, the mother reported a personal history of symptoms consistent with connective tissue disease, such as fatigue, alopecia, and xerophthalmia. Antinuclear antibodies from the mother showed titers of 1/1280 in a speckled pattern, positive anti-double-stranded DNA antibodies, and anti-Ro and Anti-La antibodies. Schirmer Test was consistent with dry eye, therefore, Systemic Lupus Erythematosus associated with Sjögren's Syndrome was diagnosed. The infant was followed up for 5 months with remission of cutaneous manifestations and normalization of laboratory tests. CONCLUSION: Although cutaneous manifestations of NLE are benign and transient in the newborn, these can be associated with other life-threatening manifestations that require an active search and prompt management by the medical team. A 25% of mothers of newborns with NLE are asymptomatic or unaware of their SLE diagnosis before delivery, so timely diagnosis of NLE leads to the diagnosis of asymptomatic mothers, improving their follow-up and treatment.

Orbital vascular malformation: Successful outcome in two patients treated with rapamycin.

Combined vascular malformations are complex vascular anomalies that have high morbidity and therefore, therapeutic strategies are hard to establish. In this report, we aim to present two pediatric cases of ocular combined vascular malformations successfully treated with rapamycin.

Persistent Nasal Infantile Hemangioma: A Surgical Treatment Algorithm.

Treatment of infantile hemangioma is usually medical. The nose is one of the most important aesthetic and functional units of the face; therefore, surgical management is preferred in persistent lesions (fibro-fatty tissue component) that do not respond to medical treatment. Herein, the authors analyze the results of surgical nasal hemangioma treatment in their center, a literature review and propose an algorithm for surgical management. A retrospective analysis of 23 persistent nasal hemangioma operated between 1996 and 2014 at our institution was made. The authors recollected the following demographic and clinical data: hemangioma subtype, phase of evolution, affected aesthetic nasal subunit, previous treatment, surgery type, complications and follow-up period. The Strasser scale was chosen for assessment of postoperative photographic results. Surgical treatment was performed. Age average was 6.8 years old (range 2-19). Mixed hemangioma was the most common subtype (83%). Surgery was mainly performed in the involution phase (87%). The most affected aesthetic subunit was nasal tip (44%). All lesions received previous medical treatment. The most common surgical technique was open rhinoplasty approach. Follow-up was an average of 26.6 months. Aesthetic results according to the Strasser method included: 3 excellent scores, 15 good, 5 regular, and none poor. Surgery was performed on patients in order to correct nasal persistent hemangiomas sequel. The nose has serious psychosocial impact and mixed infantile hemangiomas appear to have a higher rate of persistent hemangioma requiring surgery, but further studies are needed. Aesthetic outcome with surgical procedures chosen were acceptable and no complications were reported.

Bullous Henoch-Schönlein purpura. Case report. / Púrpura de Schönlein-Henoch Buloso. Caso clínico.

Henoch-Schönlein purpura (HSP) or IgA Vasculitis is the most common childhood vasculitis. The classic tetrad of signs and symptoms include palpable purpura, arthralgia, abdominal pain and renal disease. The occurrence of hemorrhagic bullae in children with HSP is rarely encountered. Objec tive: To report an unusual cutaneous manifestation of HSP in children. CASE REPORT: A 14-year-old girl complained about a 2-week painful bullous rash in both lower extremities and multiple arthral gias. There was no history of abdominal pain or urinary symptoms. In both lower extremities, there were numerous palpable purpura and hemmorrhagic bullae. In light of clinical findings, laboratory tests and skin biopsy are requested. The histopathology described intraepidermal blisters, acanthosis, spongiosis and perivascular dermal infiltrate. Direct immunofluorescence (IFD) (+) for IgA. The diagnosis of bullous HSP was made and treatment with endovenous corticosteroids was initiated. Three days after overlapping to oral corticosteroids, new ecchymotic lesions appeared in both legs. Due to the persistence of cutaneous involvement and negative control tests, azathioprine was associa ted obtaining a good response. CONCLUSION: Although bullous lesions in HSP does not add morbidity, it is often an alarming phenomenon with multiple differential diagnoses. The anti-inflamatory effect of corticoids is likely to be beneficial in the treatment of patients with severe cutaneous involvement through inhibition of proinflammatory transcription factors and decreasing the production of the metalloproteinases.

Púrpura de Schönlein-Henoch Buloso. Caso clínico / Bullous Henoch-Schönlein purpura. Case report

Resumen: Introducción: El púrpura de Schonlein-Henoch (PSH) O Vasculitis IgA es la vasculitis sistémica más frecuente de la edad pediátrica. Se manifiesta clínicamente como púrpura palpable, artralgias, dolor abdominal y compromiso renal. El púrpura palpable buloso a diferencia de lo que ocurre en la edad adulta, es muy infrecuente en la infancia. Objetivo: Reportar una forma infrecuente de presentación cutánea del PSH en niños. Caso clínico: Niña de 14 años con historia de 2 semanas con ampollas dolorosas múltiples y confluentes en ambas extremidades inferiores asociado a artralgias. A la histo-patología destacan vesículas intracórneas, epidermis con acantosis y espongiosis e infiltrado dérmico perivascular. Inmunofluorescencia directa (+) para IgA. Se plantea el diagnóstico de PSH ampollar y se realiza tratamiento inicial con corticoides intravenosos. A los tres días del traslape a corticoides orales aparecen nuevas lesiones equimóticas en ambas piernas. Se decide asociar azatriopina e iniciar descenso de corticoides, obteniéndose buena respuesta. Conclusión: Si bien la formación de bulas en el PSH no agrega morbilidad, suele ser un fenómeno alarmante que requiere realizar diagnóstico di ferencial con otras patologías. El uso de corticoides estaría indicado en estos casos ya que disminuiría la producción de las metaloproteinsas responsables de la formación de las bulas.

Abstract: Henoch-Schönlein purpura (HSP) or IgA Vasculitis is the most common childhood vasculitis. The classic tetrad of signs and symptoms include palpable purpura, arthralgia, abdominal pain and renal disease. The occurrence of hemorrhagic bullae in children with HSP is rarely encountered. Objec tive: To report an unusual cutaneous manifestation of HSP in children. Case report: A 14-year-old girl complained about a 2-week painful bullous rash in both lower extremities and multiple arthral gias. There was no history of abdominal pain or urinary symptoms. In both lower extremities, there were numerous palpable purpura and hemmorrhagic bullae. In light of clinical findings, laboratory tests and skin biopsy are requested. The histopathology described intraepidermal blisters, acanthosis, spongiosis and perivascular dermal infiltrate. Direct immunofluorescence (IFD) (+) for IgA. The diagnosis of bullous HSP was made and treatment with endovenous corticosteroids was initiated. Three days after overlapping to oral corticosteroids, new ecchymotic lesions appeared in both legs. Due to the persistence of cutaneous involvement and negative control tests, azathioprine was associa ted obtaining a good response. Conclusion: Although bullous lesions in HSP does not add morbidity, it is often an alarming phenomenon with multiple differential diagnoses. The anti-inflamatory effect of corticoids is likely to be beneficial in the treatment of patients with severe cutaneous involvement through inhibition of proinflammatory transcription factors and decreasing the production of the metalloproteinases.

A 6-week-old boy with annular skin lesions. Neonatal lupus erythematosus.

A 6-week-old, otherwise healthy boy presented to the dermatology clinic for evaluation of an eruption involving his scalp, face, and trunk. The truncal lesions had been present for several weeks, and the facial and scalp lesions were noticed 5 days prior to presentation. The eruption was asymptomatic without scratching or discomfort noted by his mother. Past medical history was remarkable for preterm delivery due to maternal hypertension during pregnancy. The infant was thriving and gaining weight appropriately. There was no family history of cutaneous or autoimmune disease. No one in the family had a recent tinea infection. On physical exam, he was a well-appearing, vigorous infant. There were multiple erythematous papules and annular plaques involving his left pre-auricular and post-auricular areas, scalp, upper chest, and right abdominal wall (Figures 1 and 2). No other cutaneous or mucus membrane lesions were noted. His cardiac, lung, and abdominal exams were normal.

A 3-year-old girl with a painful skin eruption.

CME EDUCATIONAL OBJECTIVES1.Identify clinical lesions of shingles.2.Describe the importance of the attenuated varicella vaccine and its impact on shingles presentation.3.Discuss treatment options for patients with shingles. A 3-year-old, otherwise healthy female, presented to the dermatology clinic for evaluation of a painful eruption on her right arm and back. It had been present for 6 days, and had started as a single blister on her right fourth digit. Over several days, new lesions appeared on her right hand, forearm, arm, and back. All lesions were painful and pruritic. She was afebrile and otherwise felt well. Her vaccinations were all up to date. A review of systems was unremarkable; family history was noncontributory.