ABSTRACT
Cutaneous manifestations are common in monogenic immune disorders, including both infectious and non-infectious etiologies. We report follow-up of a case initially published in Pediatric Dermatology in 2001 of a 13-year-old boy with a history of inflammatory skin lesions and neutropenia who developed neutrophilic dermatoses precipitated by G-CSF. Whole exome sequencing performed at 36 years of age revealed a gain-of-function mutation in the WAS gene, leading to a diagnosis of X-linked neutropenia. This case report provides closure on a decades-long diagnostic odyssey and underscores the importance of genetic sequencing in patients who present with unusual dermatologic findings.
Subject(s)
Neutropenia , Skin Diseases , Abscess/diagnosis , Abscess/genetics , Adolescent , Child , Humans , Male , Neutropenia/diagnosis , Neutropenia/genetics , Exome SequencingABSTRACT
We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the ß subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 ß subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.
Subject(s)
Adaptor Protein Complex 1/genetics , Adaptor Protein Complex beta Subunits/genetics , Deafness/genetics , Genes, Recessive/genetics , Ichthyosis/genetics , Mutation/genetics , Photophobia/genetics , Cell Differentiation/genetics , Cell Proliferation/genetics , Female , Hearing Loss/genetics , Humans , Male , Phenotype , Protein Subunits/genetics , Protein Transport/genetics , Thrombocytopenia/geneticsSubject(s)
Gain of Function Mutation , Genes, Dominant , Hypereosinophilic Syndrome/diagnosis , Hypereosinophilic Syndrome/etiology , Immune System Diseases/diagnosis , Immune System Diseases/etiology , Janus Kinase 1/genetics , Alleles , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Germ-Line Mutation , Humans , Hypereosinophilic Syndrome/drug therapy , Immune System Diseases/drug therapy , Immunomodulation/genetics , Janus Kinase 1/chemistry , Male , Pedigree , Phenotype , Exome SequencingABSTRACT
OBJECTIVES: Clinicians need to be aware of the growing list of defined monogenic etiologies of autoimmune diseases. This is particularly relevant when evaluating children, as these rare monogenic forms of autoimmunity tend to present very early in life. METHODS AND RESULTS: By harnessing the transformative power of next generation sequencing, we made the unifying diagnosis of RAS-associated autoimmune leukoproliferative disease (RALD), caused by the somatic gain-of-function p.G13C KRAS mutation, in a boy with the seemingly unrelated immune dysregulatory conditions of Rosai-Dorfman and systemic lupus erythematosus (SLE). CONCLUSIONS: This case expands our understanding of the clinical phenotypes associated with the extremely rare condition of RALD, and emphasizes the importance of always considering the possibility of a monogenic cause for autoimmunity, particularly when the disease manifestations begin early in life and do not follow a typical clinical course.
Subject(s)
Autoimmunity/genetics , Histiocytosis, Sinus/genetics , Lupus Erythematosus, Systemic/genetics , Mutation/genetics , Mutation/immunology , Proto-Oncogene Proteins p21(ras)/genetics , Adolescent , Autoimmunity/immunology , Histiocytosis, Sinus/immunology , Humans , Lupus Erythematosus, Systemic/immunology , Male , SyndromeABSTRACT
Vascular anomalies represent a spectrum of disorders from a simple "birthmark" to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists. Classification schemes provide a consistent terminology and serve as a guide for pathologists, clinicians, and researchers. One of the goals of the International Society for the Study of Vascular Anomalies (ISSVA) is to achieve a uniform classification. The last classification (1997) stratified vascular lesions into vascular malformations and proliferative vascular lesions (tumors). However, additional disease entities have since been identified that are complex and less easily classified by generic headings, such as capillary malformation, venous malformation, lymphatic malformation, etc. We hereby present the updated official ISSVA classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and lists the main recognized vascular tumors, classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the "Simple Vascular Malformations" section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as "truncular" malformations); the second groups lesions of uncertain or debated nature (tumor versus malformation). The known genetic defects underlying vascular anomalies are included in an appendix. This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available.
Subject(s)
Biomedical Research , Guidelines as Topic , Societies, Medical , Vascular Malformations/classification , HumansSubject(s)
Caspases , Homozygote , Mutation , Neoplasm Proteins , Severe Combined Immunodeficiency/genetics , Adolescent , Caspases/genetics , Caspases/immunology , Female , Humans , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathologyABSTRACT
Helicobacter bilis, an unusual cause of chronic infections in patients with X-linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection.
Subject(s)
Agammaglobulinemia/drug therapy , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Genetic Diseases, X-Linked/drug therapy , Helicobacter Infections/drug therapy , Helicobacter/drug effects , Ofloxacin/therapeutic use , beta-Lactams/therapeutic use , Adolescent , Adult , Agammaglobulinemia/complications , Agammaglobulinemia/diagnosis , Agammaglobulinemia/pathology , Chronic Disease , Ertapenem , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/pathology , Helicobacter/genetics , Helicobacter/pathogenicity , Helicobacter Infections/complications , Helicobacter Infections/diagnosis , Helicobacter Infections/pathology , Humans , Male , Phylogeny , Treatment OutcomeSubject(s)
Graft Rejection/diagnosis , Kidney Transplantation/adverse effects , Pemphigoid, Bullous/diagnosis , Biopsy, Needle , Child , Chronic Disease , Diagnosis, Differential , Humans , Immunohistochemistry , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/surgery , Kidney Transplantation/methods , Male , Monitoring, Physiologic/methods , Pemphigoid, Bullous/drug therapy , Pemphigoid, Bullous/etiology , Prednisone/therapeutic use , Rare Diseases , Severity of Illness Index , Transplantation, Homologous , Treatment OutcomeABSTRACT
QUESTION: I see many children with infantile hemangiomas and have read about new therapeutic options such as propranolol. Is this medication effective and safe for treating hemangiomas in children? ANSWER: Most infantile hemangiomas resolve spontaneously without any need for therapy. In many case series, propranolol has been shown to be effective and safe in treating hemangiomas that cause complications. Further studies are required to determine the optimal dose and duration of propranolol treatment for problematic hemangiomas.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Hemangioma/drug therapy , Propranolol/therapeutic use , Adrenergic beta-Antagonists/adverse effects , Child , HumansSubject(s)
Dermatitis, Allergic Contact/diagnosis , Exanthema/diagnosis , Nickel/adverse effects , Pruritus/diagnosis , Acute Disease , Child, Preschool , Dermatitis, Allergic Contact/drug therapy , Humans , Male , Methylprednisolone/therapeutic use , Prednisone/therapeutic use , Pyloric Antrum/diagnostic imaging , Radiography , Treatment OutcomeABSTRACT
AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.
Subject(s)
Cerebral Arterial Diseases/genetics , Cerebral Arterial Diseases/physiopathology , Homeostasis/physiology , Monomeric GTP-Binding Proteins/genetics , Proteins/genetics , Carotid Stenosis/genetics , Carotid Stenosis/physiopathology , Child , Child, Preschool , DNA Mutational Analysis , Exodeoxyribonucleases , Female , Humans , Infant , Male , Phosphoproteins , Point Mutation/genetics , SAM Domain and HD Domain-Containing Protein 1ABSTRACT
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Immunity, Innate , Monomeric GTP-Binding Proteins/genetics , Amino Acid Substitution , Brain Diseases, Metabolic, Inborn/immunology , Humans , Monomeric GTP-Binding Proteins/immunology , SAM Domain and HD Domain-Containing Protein 1ABSTRACT
We describe asymptomatic bone cysts in the right humerus of a 17-year-old boy with Darier disease. The cysts were found when a radiographic skeletal survey was performed to monitor for adverse effects of oral retinoid therapy. Magnetic resonance imaging was used to confirm that the lesions were cystic and to delineate their extent. The literature was reviewed for previous reports of this association.
Subject(s)
Bone Cysts/diagnosis , Darier Disease/complications , Humerus , Magnetic Resonance Imaging , Adolescent , Humans , MaleABSTRACT
Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome is a recently described autosomal recessive disorder associated with predominantly antibody negative, insulin-dependent diabetes mellitus. In order to identify the genetic basis of PHID and study its relationship with glucose metabolism, we performed homozygosity mapping in five unrelated families followed by candidate gene sequencing. Five loss-of-function mutations were identified in the SLC29A3 gene which encodes a member of a highly conserved protein family that transports nucleosides, nucleobases and nucleoside analogue drugs, hENT3. We show that PHID is allelic with a related syndrome without diabetes mellitus, H syndrome. The interaction of SLC29A3 with insulin signaling pathways was then studied using an established model in Drosophila melanogaster. Ubiquitous knockdown of the Drosophila ortholog of hENT3, dENT1 is lethal under stringent conditions; whereas milder knockdown induced scutellar bristle phenotypes similar to those previously reported in the knockdown of the Drosophila ortholog of the Islet gene. A cellular growth assay showed a reduction of cell size/number which could be rescued or enhanced by manipulation of the Drosophila insulin receptor and its downstream signaling effectors, dPI3K and dAkt. In summary, inactivating mutations in SLC29A3 cause a syndromic form of insulin-dependent diabetes in humans and in Drosophila profoundly affect cell size/number through interactions with the insulin signaling pathway. These data suggest that further investigation of the role of SLC29A3 in glucose metabolism is a priority for diabetes research.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Hypertrichosis/genetics , Insulin/metabolism , Mutation , Nucleoside Transport Proteins/genetics , Signal Transduction , Amino Acid Sequence , Animals , Base Sequence , Diabetes Mellitus, Type 1/metabolism , Disease Models, Animal , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Female , Humans , Hypertrichosis/metabolism , Insulin/genetics , Male , Molecular Sequence Data , Nucleoside Transport Proteins/chemistry , Nucleoside Transport Proteins/metabolism , Pedigree , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Sequence Alignment , Skin PigmentationABSTRACT
Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.
Subject(s)
Immunoglobulin Variable Region/genetics , Mutation , Recombinant Proteins/genetics , Vascular Malformations/genetics , Vein of Galen Malformations/genetics , Arteriovenous Malformations , Family , Humans , Phenotype , Single-Chain Antibodies , Syndrome , p120 GTPase Activating ProteinABSTRACT
BACKGROUND: PHACE syndrome (Online Mendelian Inheritance in Man database No. 606519) refers to the association of large, plaquelike, or segmental hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects, supraumbilical raphe, or both. OBJECTIVE: The underlying pathogenesis of PHACE is unknown. A strong female predominance exists, leading some to suggest the possibility of X-linked dominant inheritance, with lethality in male patients. However, no familial cases have been reported, and disease severity among affected male patients has not been systematically studied. METHODS: We compared the incidence of syndrome-associated anomalies between 17 new and 42 published reports of male patients with PHACE versus 213 published reports of female patients with PHACE. RESULTS: A statistically significant difference was found only for structural brain anomalies, which were somewhat more common in male patients. LIMITATIONS: This was a retrospective study. Information was limited on some new and many previously reported cases. CONCLUSIONS: Overall, our results show no convincing trend toward greater or lesser disease severity among affected male patients with PHACE.
Subject(s)
Abnormalities, Multiple/epidemiology , Facial Neoplasms/complications , Hemangioma/complications , Brain/abnormalities , Developmental Disabilities/epidemiology , Eye Abnormalities/epidemiology , Female , Humans , Incidence , Infant , Male , Retrospective Studies , Severity of Illness Index , Sex Distribution , Syndrome , Vascular Malformations/epidemiologyABSTRACT
A novel pigmented dermatosis was observed in four unrelated boys, three of whom had insulin-dependent diabetes. Three patients were the offspring of consanguineous parents. All four boys had pigmented hypertrichotic patches or induration on the upper inner thighs, with variable involvement of the genitalia, trunk, and limbs. Two boys had episcleritis and orbital proptosis with similar facies and musculoskeletal abnormalities including clinodactyly, flat feet, and short stature. One child had paraaortic and inguinal lymphadenopathy and three patients had an enlarged liver and spleen. A large, swollen pancreas was observed on ultrasound imaging in one patient with insulin dependent diabetes who also had echocardiographic evidence of pericardial inflammation. Three boys had elevated laboratory markers of inflammation. Biopsy specimens from the skin and orbit showed a chronic inflammatory cell infiltrate composed of polyclonal lymphocytes, histiocytes, and plasma cells; fibrosis was observed in two patients, one of whom had previously received radiation therapy to the orbit. Two boys responded to treatment with subcutaneous interferon-alpha, combined with a short course of oral prednisone in the child without diabetes. We believe these inflammatory pigmented skin lesions represent a unique dermatosis associated with diabetes mellitus and systemic disease. The pathogenesis is unknown. The presence of consanguinity in three of four families, and similar dysmorphic features in two boys, suggest a genetic disorder, possibly with autosomal recessive inheritance.
Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Hyperpigmentation/complications , Hyperpigmentation/genetics , Hypertrichosis/complications , Hypertrichosis/genetics , Adolescent , Child , Consanguinity , Diabetes Mellitus, Type 1/pathology , Humans , Hyperpigmentation/pathology , Hypertrichosis/pathology , MaleABSTRACT
BACKGROUND: Keratosis pilaris is a common skin disorder of childhood that often improves with age. Less common variants of keratosis pilaris include keratosis pilaris atrophicans and atrophodermia vermiculata. OBSERVATIONS: In this case series from dermatology practices in the United States, Canada, Israel, and Australia, the clinical characteristics of 27 patients with keratosis pilaris rubra are described. Marked erythema with follicular prominence was noted in all patients, most commonly affecting the lateral aspects of the cheeks and the proximal arms and legs, with both more marked erythema and widespread extent of disease than in keratosis pilaris. The mean age at onset was 5 years (range, birth to 12 years). Sixty-three percent of patients were male. No patients had atrophy or scarring from their lesions. Various treatments were used, with minimal or no improvement in most cases. CONCLUSIONS: Keratosis pilaris rubra is a variant of keratosis pilaris, with more prominent erythema and with more widespread areas of skin involvement in some cases, but without the atrophy or hyperpigmentation noted in certain keratosis pilaris variants. It seems to be a relatively common but uncommonly reported condition.