sirolimus and Abnormalities--Multiple

Keratosis pilaris rubra (KPR) is a subtype of keratosis pilaris (KP) presenting with numerous "grainlike" follicular papules in a background of confluent erythema most often affecting the face and upper extremities with persistence beyond puberty. Treatment has remained challenging with inconsistent benefit from topical therapies such as emollients, keratolytics, corticosteroids, and retinoids, though case reports documenting success with pulsed dye laser therapy have been found. We present a case of KPR in a 15-year-old boy who was successfully treated with topical sirolimus 1% cream.

Topics: Abnormalities, Multiple; Adolescent; Darier Disease; Emollients; Exanthema; Eyebrows; Humans; Immunosuppressive Agents; Male; Pityriasis Rubra Pilaris; Sirolimus

Topics: Abnormalities, Multiple; Autophagosomes; Autophagy; Chromosome Deletion; Chromosomes, Human, Pair 17; Epigenesis, Genetic; Humans; Intellectual Disability; Lysine; Lysosomes; Reactive Oxygen Species; Sirolimus; Superoxide Dismutase-1; TOR Serine-Threonine Kinases

PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth.. Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy.. Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.. This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Female; Growth Disorders; Humans; Male; Middle Aged; Mutation; Phenotype; Phosphatidylinositol 3-Kinases; Sirolimus; TOR Serine-Threonine Kinases

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.

Topics: Abnormalities, Multiple; Base Sequence; Bronchodilator Agents; Class I Phosphatidylinositol 3-Kinases; Diagnosis, Differential; Enteral Nutrition; Humans; Immunosuppressive Agents; Infant, Newborn; Lipoma; Male; Megalencephaly; Musculoskeletal Abnormalities; Mutation; Nevus; Phenotype; Respiration, Artificial; Sirolimus; Skin Diseases, Vascular; Telangiectasis; Vascular Malformations

One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.. Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs).. A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects.. These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

Topics: Abnormalities, Multiple; Adolescent; Biomarkers; Child; Face; Female; Hematologic Diseases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Sirolimus; T-Lymphocytes, Regulatory; Vestibular Diseases

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Topics: Abnormalities, Multiple; Anemia, Iron-Deficiency; Child; Consanguinity; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Heart Septal Defects, Atrial; Humans; Male; Neoplasms, Multiple Primary; Nevus, Blue; Oral Ulcer; Sirolimus; Skin Neoplasms; Tongue Neoplasms

Management of patients with complex vascular anomalies (VAs) is often associated with significant morbidity and mortality because of the lack of effective treatment modalities that may lead to significant improvement of the disease and/or healing. Recently, reports of treatment of patients with complex VAs with sirolimus revealed encouraging results. Sirolimus inhibits the mammalian target of rapamycin, which acts as a master switch of numerous cellular processes. We report a successful use of sirolimus for the treatment of a patient with a complex CLVM of the trunk and the right lower extremity believed to be untreatable. Our patient had 44 hospitalizations during the 10-year period, with various unsuccessful treatments and continuous deterioration of his clinical condition, ending up in a wheelchair. His condition reversed to normal everyday activities 9 months after initiation of sirolimus therapy. We conclude that sirolimus is a very promising therapeutic option for children with complex VAs of capillary-lymphatico-venous type.

Topics: Abnormalities, Multiple; Follow-Up Studies; Humans; Infant, Newborn; Lymphatic Vessels; Male; Sirolimus; Vascular Malformations; Veins

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder that can affect every organ of the body, most commonly the brain, kidneys, heart, and lungs. The TSC mutation results in abnormal cellular proliferation and differentiation, which are responsible for hamartomatous lesions that affect the brain, kidney, heart, and lungs. mTOR (mammalian target of rapamycin) is a protein kinase that regulates the abnormal cellular proliferation and differentiation. Consequently, mTOR inhibitors are being studied to treat the subependymal giant-cell astrocytomas and renal angiomyolipomas that are commonly seen with TSC. We describe here the case of a patient with significant regression of a cardiac rhabdomyoma after receiving everolimus, an mTOR inhibitor. This finding suggests a possible novel therapy for patients with clinically significant cardiac rhabdomyomas.

Topics: Abnormalities, Multiple; Astrocytoma; Child; Echocardiography, Doppler; Everolimus; Follow-Up Studies; Heart Neoplasms; Humans; Immunosuppressive Agents; Male; Rhabdomyoma; Sirolimus; Treatment Outcome; Tuberous Sclerosis; Tumor Burden