Julie S. Prendiville

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

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.

Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies

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.

Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast‐flow vascular anomalies are caused by RASA1 mutations

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. Hum Mutat 29(7), 959–965, 2008.

Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.

A retrospective analysis of 21 consecutive patients hospitalized with either Stevens-Johnson syndrome or toxic epidermal necrolysis was carried out to assess morbidity and mortality rates and to establish the value of a specific management practice. Fourteen children with Stevens-Johnson syndrome and seven with toxic epidermal necrolysis were cared for at the Childrens Memorial Hospital, Chicago, between 1978 and 1988. All were managed in a well-staffed medical ward or, when necessary, in the pediatric intensive care unit. Supportive measures included reverse barrier isolation, intravenous fluids and nutritional support, meticulous skin care, early detection and treatment of infection, and daily ophthalmologic examination. No patient was treated with systemic steroids. The mortality rate was zero. Eye complications, consisting of dry eyes or mild chronic symblepharon, were the most significant long-term sequelae.

Central nervous system involvement in neonatal lupus erythematosus.

Abstract: Computerized tomography (CT) of the brain was performed in 10 of 11 consecutive infants with neonatal lupus erythematosus (NLE) (five boys and six girls). Ten of the 11 infants had brain neurosonography. Nine of 10 infants had abnormal CT scans. There was diffuse, markedly reduced attenuation of the cerebral white matter in four infants studied in the first week of life, and also in an infant 5 weeks of age. Patchy reduced subcortical white matter attenuation was observed in another 5‐week‐old infant. Basal ganglia calcifications were present in two infants at 2 months of age, one of whom also had mild ventriculomegaly. A patient with macrocephaly studied at 4 months of age had enlarged ventricles and subarachnoid spaces consistent with benign macrocephaly of infancy. Cerebral ultrasound examination was abnormal in all five infants studied in the first week of life and in one infant at 2 months of age. Findings included subependymal cysts (4), echogenic white matter (3), and echogenic lenticulostriate vessels (3). Apart from one case of macrocephaly, there was no clinical evidence of neurologic disease and the subsequent development of these infants has been normal. Subclinical central nervous system (CNS) disease in NLE is likely to be a transient phenomenon that resolves as maternal antibodies are cleared from the infants circulation. It is important to be aware of these neuroimaging abnormalities to avoid misdiagnosis of congenital viral infection in a newborn with multisystem NLE. The potential for neurologic sequelae is uncertain.

SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway

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.

Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature.

BACKGROUND Chronic granulomatous disease represents a group of genetic disorders in which impaired intracellular microbial killing by phagocytes leads to recurrent bacterial and fungal infections and granuloma formation. Cutaneous disease occurs in 60% to 70% of cases. The characteristic histologic finding of pigmented lipid macrophages in visceral granulomas has not been described previously in the skin. OBJECTIVE Our purpose was to review our experience of skin disorders in chronic granulomatous disease. METHODS We studied the clinical and histologic findings in four patients with chronic granulomatous disease and unusual skin lesions. We reviewed the skin disorders seen in five additional patients with chronic granulomatous disease referred to the pediatric dermatology clinic. The literature was reviewed for previously reported cutaneous manifestations of chronic granulomatous disease. RESULTS A teenage boy with chronic granulomatous colitis had nonulcerating cutaneous granulomas from which no organisms were isolated. Histologic examination of both skin and bowel revealed the characteristic golden-yellow granular pigment in macrophages. A second boy had cutaneous aspergillosis involving the left foot; histologic examination revealed macrophages containing yellow-brown pigment at the periphery of the granulomatous inflammation. Two children had vesicular skin lesions. These lesions were recurrent in one boy for several years. In the second child they were associated with fatal intracranial and pulmonary infection. Histologic examination in both cases revealed a subcorneal polymorphonuclear infiltrate and perivascular macrophages containing yellow-brown pigment. Cultures were either negative or revealed organisms that are normally nonpathogenic skin commensals, such as coagulase-negative staphylococci. CONCLUSION The cutaneous manifestations of chronic granulomatous disease encompass a variety of infections and inflammatory lesions. Diagnostic and therapeutic problems may arise because of difficulty in isolating a causative organism. The characteristic pigmented macrophages of visceral granulomas can also be found in skin lesions.

Kindler syndrome: Report of two cases and review of the literature

Abstract: We evaluated two patients Mrith hereditary bullous polkiloderma. Both had acral buliae, generalized poiidloderma with prominent atrophy, and acral keratoses. One patient, with sporadic disease, hj, in addition, urethral and subgiottic stenoses, weiabing of digits, and poor dentition. Hie other patient, whose disease was dominantiy inherited, had koiionychia. The resuits of cutaneous histopathology, electron microscopy, and immunofiuorescice mapping studies are presented, it is possible that Kindler syndrome and Wearys hereditary acrokeratotic poikiioderma are variants of the same disease.

Intracerebral large artery disease in Aicardi–Goutières syndrome implicates SAMHD1 in vascular homeostasis

Aim  To describe a spectrum of intracerebral large artery disease in Aicardi–Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1.

Detection and Genotyping of Varicella-Zoster Virus by TaqMan Allelic Discrimination Real-Time PCR

ABSTRACT A proportion of individuals vaccinated with live attenuated Oka varicella-zoster virus (VZV) vaccine subsequently develop attenuated chicken pox and/or herpes zoster. To determine whether postvaccination varicella infections are caused by vaccine or wild-type virus, a simple method for distinguishing the vaccine strain from wild-type virus is required. We have developed a TaqMan real-time PCR assay to detect and differentiate wild-type virus from Oka vaccine strains of VZV. The assay utilized two fluorogenic, minor groove binding probes targeted to a single nucleotide polymorphism in open reading frame 62 that distinguishes the Oka vaccine from wild-type strains. VZV DNA could be genotyped and quantified within minutes of thermocycling completion due to real-time monitoring of PCR product formation and allelic discrimination analysis. The allelic discrimination assay was performed in parallel with two standard PCR-restriction fragment length polymorphism (RFLP) methods on 136 clinical and laboratory VZV strains from Canada, Australia, and Japan. The TaqMan assay exhibited a genotyping accuracy of 100% and, when compared to both PCR-RFLP methods, was 100 times more sensitive. In addition, the method was technically simpler and more rapid. The TaqMan assay also allows for high-throughput genotyping, making it ideal for epidemiologic study of the live attenuated varicella vaccine.