LUMBAR syndrome-OEIS complex overlap: A case series and review.

We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella coined recurrent constellations of embryonic malformations (RCEMs). The RCEMs represent a phenotypically overlapping spectrum of rare disorders of caudal dysgenesis with unknown cause but likely shared pathogenesis. It has recently been proposed that LUMBAR be considered an RCEM. This report of infants with combined features of OEIS and LUMBAR is the first to demonstrate an overlap between LUMBAR and another RCEM, which supports LUMBAR's inclusion within the RCEM spectrum.

Risk factors for morphoea disease severity: a retrospective review of 114 paediatric patients.

BACKGROUND: Morphoea is a rare fibrosing disease of the skin and subcutaneous tissue with an unpredictable disease course, running the spectrum from mild skin involvement to severe disfigurement or extracutaneous complications. OBJECTIVES: Our objective was to describe the natural history of paediatric morphoea and determine patient variables that were associated with severe disease. PATIENTS AND METHODS: We conducted a retrospective chart review of patients with morphoea seen in one paediatric hospital system. Information about demographics, clinical characteristics, disease course and treatment were collected. Statistical analysis was performed using appropriate univariate tests and a multivariable model. RESULTS: One hundred and fourteen patients met study inclusion criteria. The female : male ratio was 2·6 : 1, and the median age of onset was 7 years old. There were 55 patients (48%) with linear morphoea, 38 patients (33%) with circumscribed morphoea, 12 patients (11%) with generalized morphoea, and nine patients (8%) with mixed morphoea. Neurological symptoms and joint involvement were present in 27 subjects (24%). Extracutaneous manifestations occurred in 38% of subjects with linear morphoea, compared with 15% with generalized morphoea and 3% with circumscribed morphoea (P = 0·0001). Thirty-six per cent of children with disease onset prior to 10 years of age and 5% of children with disease onset after 10 years of age had extracutaneous manifestations (P = 0·0002). Both linear morphoea and early-onset disease were significantly associated with extracutaneous involvement in a multivariable model. CONCLUSIONS: Children with linear morphoea and disease onset before 10 years of age should be monitored closely for extracutaneous manifestations and need early treatment with systemic medications to prevent disease complications.

Demographic and clinical characteristics of cutaneous lupus erythematosus at a paediatric dermatology referral centre.

BACKGROUND: Paediatric cutaneous lupus erythematosus (CLE) is uncommon and inadequately described in the literature. Similar to adults, children with CLE develop LE-specific and/or LE-nonspecific skin findings. Similarities and differences in demographics and clinical course between paediatric and adult CLE have not been sufficiently described. OBJECTIVES: To detail the demographic and clinical features of paediatric CLE and compare these findings with those reported in the adult literature. METHODS: A retrospective chart review was performed of 53 children seen in a paediatric dermatology clinic with cutaneous manifestations of LE. RESULTS: Patients presented with all five major subtypes of CLE, with some notable differences from adult CLE and previously published reports of paediatric CLE. Progression from discoid LE to systemic LE (SLE) did not occur in our cohort. Patients with subacute CLE were more likely than adults to have lesions below the waist as well as concomitant SLE. Sex distribution for CLE in our study was equal prior to puberty and female predominant in post-pubertal patients. CONCLUSIONS: Children with CLE have variable clinical presentations and progression to SLE that may be different from adult disease. Specifically, children with acute and subacute CLE may be more likely than adults to have systemic disease; therefore, patients with these subtypes should be monitored closely for evidence of SLE. Study limitations included small patient numbers that may limit the ability to generalize these data and relatively short follow-up intervals.

Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.

BACKGROUND: The RASopathies are a class of human genetic syndromes caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Costello syndrome (CS) is a RASopathy caused by mutations in the HRAS gene, a key regulator of signal transduction. OBJECTIVE: To quantify the specific cutaneous phenotype observed in 46 individuals with Costello syndrome with confirmed HRAS mutations. METHODS: This was a cross-sectional study. Dermatological surveys were designed by the authors and were completed by parents of mutation-positive individuals with CS at the Costello Syndrome Family Network (CSFN) conferences in 2007 and 2009. Dermatological examinations were performed by the authors at the CSFN conferences. RESULTS: Cutaneous papillomas were reported in 33 of the 46 (72%) participants, with age of onset ranging from infancy to 22years. Individuals with CS are more likely than patients with cardiofaciocutaneous syndrome (CFC) to present with cutaneous papillomas (72% vs. 5%, P<0·001) and palmoplantar keratoderma (76% vs. 36%, P<0·001). Individuals with CS are less likely than individuals with CFC to present with sparse or absent eyebrows (9% vs. 90%, P<0·001) or keratosis pilaris (33% vs. 80%, P=0·001). This study also identified that loose, redundant skin on the hands and feet, 'stippled' dermatoglyphs (pachydermatoglyphia) on the fingertips (eight of 26, 31%) and acanthosis nigricans (17 of 46, 37%) are frequent features of CS. CONCLUSIONS: While there is significant phenotypic overlap among syndromes of the Ras/MAPK pathway, individuals with CS are more likely than individuals with CFC syndrome to present with cutaneous papillomas, palmoplantar keratoderma and full eyebrows, and are less likely to present with ulerythema ophryogenes, keratosis pilaris or multiple naevi. The dermatological features of CS, a Ras dysregulation syndrome, share many features with cutaneous paraneoplastic syndromes. This may provide further insight into the role of Ras signalling in cutaneous paraneoplastic syndromes.

Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome.

BACKGROUND: The RASopathies are a class of human genetic syndromes that are caused by germline mutations in genes which encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Cardiofaciocutaneous (CFC) syndrome is characterized by distinctive craniofacial features, congenital heart defects, and abnormalities of the skin and hair. OBJECTIVES: Systematically to characterize the spectrum of dermatological findings in mutation-positive individuals with CFC syndrome. METHODS: Dermatological surveys were designed by the authors and distributed to the study participants through CFC International or directly by the authors (K.A.R. and D.H.S.) between July 2006 and August 2009. A second follow-up survey was collected between December 2007 and August 2009. When available, digital images and medical records of the participants were obtained. Study participants included individuals with CFC syndrome who have a mutation in BRAF, MAP2K1, MAP2K2 or KRAS. RESULTS: Individuals with CFC syndrome have a variety of dermatological manifestations caused by dysregulation of the MAPK pathway in development. Numerous acquired melanocytic naevi were one of the most striking features: more than 50 naevi were reported by 23% (14/61) of participants and of those, more than 100 naevi were reported by 36% (5/14). Keratosis pilaris was reported in 80% (49/61) of cases. Ulerythema ophryogenes was common, occurring in 90% (55/61). Infantile haemangiomas occurred at a greater frequency, 26% (16/61), as compared with the general population. CONCLUSIONS: CFC syndrome has a complex dermatological phenotype with many cutaneous features, some of which allow it to be differentiated from the other Ras/MAPK pathway syndromes. Multiple café-au-lait macules and papillomas were not identified in this CFC cohort, helping to distinguish CFC from other RASopathies such as neurofibromatosis type 1 and Costello syndrome.

X Chromosome-Inactivation Patterns in 31 Individuals with PHACE Syndrome.

Segmental hemangiomas of the head and neck can be associated with multiple congenital anomalies in the disorder known as PHACE syndrome (OMIM 606519) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies). All reported cases of PHACE syndrome to date have been sporadic, and the genetic basis of this disorder has not yet been established. PHACE syndrome has a striking female predominance which has raised the question of X-linked inheritance. In this study, the X chromosome-inactivation (XCI) patterns of 31 females with PHACE syndrome and their mothers were analyzed using blood-derived DNA and X-chromosome locus methylation assay. This study was performed to test the hypothesis that some cases of PHACE syndrome are due to X-linked inheritance and favorable skewing in the mothers may protect against a severe phenotype, but the clinical phenotype may be unmasked in daughters with a random pattern of X-inactivation. XCI analysis was informative in 27/31 mothers. Our results identified skewed XCI in 5 of 27 (19%) informative mothers, which is not statistically significant with a p value of 0.41. None of the mothers reported significant medical problems, although a full PHACE work-up has not been performed in these individuals. Skewed XCI in the mothers of children with PHACE was identified in only a minority of cases. Based on these results, genetic heterogeneity is likely in PHACE syndrome, although it is possible a subset of cases are caused by a mutation in an X-linked gene.

Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome.

BACKGROUND AND PURPOSE: Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome. MATERIALS AND METHODS: Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities. RESULTS: By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections. CONCLUSIONS: The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.

Arterial stents in the management of neurofibromatosis and renovascular hypertension in a pediatric patient: case report of a new treatment modality.

A 17-year-old male with neurofibromatosis presented with severe hypertension secondary to an abdominal aortic coarctation and bilateral renal artery stenoses. Despite previous surgical bypass grafts and aggressive medical management, including treatment with diuretics, beta-blocker, calcium channel blocker, angiotensin converting enzyme (ACE) inhibitors, and direct vasodilator agents, severe hypertension persisted. Following intravascular stent placement in the aorta and both renal arteries, blood pressures normalized.

TAG-72-reactive antibody CC49 recognizes molecules expressed by hematopoietic cell lines.

Aberrant glycosylation of mucins on the surface of adenocarcinomas leads to exposure of novel tumor-associated epitopes potentially recognizable by the immune system. Monoclonal antibodies (mAbs) have been developed against some of these epitopes. One such mAb, denoted CC49, recognizes the tumor-associated glycoprotein TAG-72. Most adenocarcinomas, including breast, colon, ovarian, prostate, and gastric, express some form of this molecule, recognizable by the CC49 antibody. The widespread distribution of the antigen on transformed cells makes the CC49 mAb a potentially powerful tool in numerous immunotherapy contexts. In the course of our studies with CC49 and certain of its molecularly engineered derivatives, we screened a number of human hematopoietic cell lines for TAG-72 expression by flow cytometry using CC49. We found that the T-cell line, Jurkat, had a higher level of CC49 mAb binding than any of the carcinoma cell lines previously evaluated in our laboratory. In addition, the myelomonocytic cell line Tf-1 and the erythroleukemia cell line K562 were also positive for CC49 mAb binding by flow-cytometric analysis. However, peripheral blood lymphocytes and certain other hematopoietic cell lines were not able to bind the CC49 mAb. Immunoblot analyses of cell extracts from the CC49 reactive lines indicated distinct protein species reactive with the CC49 antibody. In some instances, cells expressing these reactive proteins were susceptible to antibody-dependent cellular cytotoxicity using a chimeric derivative of the CC49 antibody. These results indicate that the cell membrane expression of molecules recognized by CC49 extends beyond adenocarcinomas to certain cell lines of hematopoietic origin.