Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth.

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. RESULTS: The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. CONCLUSION: Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

Tiled array-based sequencing identifies enrichment of loss-of-function variants in the highly homologous filaggrin gene in African-American children with severe atopic dermatitis.

Filaggrin (FLG) loss-of-function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population-specific. African-American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short-read alignment to FLG's high homology repeat variation. Here, we employed an array-based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well-characterized cohort of AA children with moderate-to-severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10-4 ) and ESP (1.7%; P = 3.5 × 10-5 ) suggesting a disease-enrichment effect for FLG LOF. Our results demonstrate the utility of array-based sequencing in discovering FLG LOF, including novel and population-specific, which are of higher prevalence in our AA severe AD group than previously reported.

Tinea capitis mimicking dissecting cellulitis in three children.

Tinea capitis mimicking dissecting cellulitis is a rare presentation, and there is a paucity of information regarding this presentation in the literature. Three children 10-14 years of age who presented with an unusual clinical manifestation of tinea capitis that clinically resembled dissecting cellulitis are reported. The patients were treated with systemic antifungals for 3-4 months. Treatment success was measured according to repeat fungal cultures and clinical assessment of hair regrowth at follow-up visits. All three patients had resolution of infection, with negative repeat fungal cultures and complete hair regrowth without scarring. These cases highlight a rare inflammatory subtype of tinea capitis that can be easily misdiagnosed and therefore improperly treated, prolonging the duration of infection.

Hypocellular Plaque-Like CD34-Positive Dermal Fibroma (Medallion-Like Dermal Dendrocyte Hamartoma) Presenting as a Skin-Colored Dermal Nodule.

Plaque-like CD34-positive dermal fibromas, also known as medallion-like dermal dendrocyte hamartomas (MDDHs), are a recently recognized group of congenital and acquired spindle cell neoplasms that may appear histologically similar to dermatofibrosarcoma protuberans. Recognizing the clinical heterogeneity of this neoplasm and the subtle pathologic differences are crucial to making the correct diagnosis and avoiding the aggressive surgical intervention required to treat a dermatofibrosarcoma protuberans. We present the case of a 9-year-old girl with an acquired variant of a plaque-like CD34-positive dermal fibroma without clinical epidermal change. Our case expands the clinical spectrum to include an acquired variant of a plaque-like CD34-positive dermal fibroma without clinical epidermal change. Examination of more cases is needed to determine whether all clinical variants are truly subtypes of the same neoplasm or represent distinct CD34-positive spindle cell proliferations.

Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects.

Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas. X-inactivation plays a major role in determining the range of phenotypic expression. Thus, patients can demonstrate a wide spectrum of disease severity, making accurate diagnosis more challenging. Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. We present a case of molecularly confirmed TODPD in a girl with the 47,XXX chromosomal complement and deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions. Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma, which contrasts with the dermal hypoplasia described in the only other such facial biopsy reported in the literature. The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology, which may explain the nature of many connective tissue pleotropic effects in FLNA-related disorders.

Long-term follow-up of pediatric trachyonychia.

Pediatric trachyonychia is an acquired nail disease that can cause distress to families. It is a poorly understood disease, and long-term follow-up data are lacking. We present an institutional review of 11 children with isolated pediatric trachyonychia followed over time. Children with the diagnosis of pediatric trachyonychia were identified and invited to participate. Pictures were taken on follow-up and a questionnaire was answered. Exclusion criteria include having another diagnosis at the initial visit that causes nail dystrophy. Eleven patients with the diagnosis of pediatric trachyonychia were available for follow-up. The mean age of appearance was 2.7 years (range 2-7 yrs) and the average follow-up was 66 months (range 10-126 mos). Nine patients were treated with potent topical corticosteroids, one used only petrolatum, and one took vitamin supplements. One patient was found to have an additional skin and hair diagnosis of alopecia areata on follow-up. On follow-up, 82% noted improvement of the nails, whereas 18% noted no change. A majority of cases of pediatric trachyonychia are isolated and improve with time, regardless of treatment.

Ulcerated Spitz nevus masquerading as a juvenile xanthogranuloma.

We report a case of ulcerated atypical Spitz nevi that demonstrated a yellow to light orange background under dermoscopy, which can be seen in juvenile xanthogranuloma (JXG) and is referred to as the "setting sun" appearance. This yellow to orange appearance was due to serous crusting and not histiocytic infiltration, which is seen in JXG. This case highlights overlapping dermatoscopic features between the two skin lesions and polymorphous vascular structures, which are unique to atypical Spitz nevi.

Photopneumatic therapy for the treatment of keratosis pilaris.

BACKGROUND: Current treatment options for keratosis pilaris (KP) are limited and are often found to be unsatisfactory to patients. OBJECTIVE: Pilot study to determine if photopneumatic therapy (PPx) can improve the erythema and skin texture in KP. METHODS: Ten patients with KP were treated with one session of PPx on the upper arm and then evaluated one month later for treatment efficacy. RESULTS: Average investigator-assessed improvement was 27% in erythema and 56% in skin texture roughness. Average patient self-reported improvement was 52% in erythema and 53% in skin texture. The mean satisfaction score was 6.3 on a scale of 1 to 10 (median 7.5) and 8 out of 10 participants reported they would choose to receive PPx for their KP again in the future. LIMITATIONS: Small number of patients, short follow-up period, and lack of blinding of the examiner and the patients making recall bias possible. CONCLUSIONS: One treatment of PPx improved both the erythema and redness associated with KP over at least a one month period.

Heel-line hyperpigmentation: a variant of sock-line hyperpigmentation after the use of heel-length socks.

Two infants developed hyperpigmented curvilinear patches on the posterior heel after wearing heel-length socks. Both of the patient's lesions improved after discontinuing the use of the heel-length socks. Hyperpigmented patches called sock-line or mitten-line hyperpigmentation have been reported at sites of tight elastic bands from socks or mittens in infants on the calves and wrists. Recognizing this clinical entity is important to differentiate it from other causes of linear lesions such as child abuse or amniotic band syndrome.

Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics.

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

A prospective assessment of food and nutrient intake in a population of Malawian children at risk for kwashiorkor.

OBJECTIVE: To determine what foods, nutrients, and dietary patterns are associated with development of kwashiorkor in populations of vulnerable 1- to 3-year-old Malawian children. PATIENTS AND METHODS: This was a prospective observational study conducted in 8 rural villages. Upon enrollment, demographic, anthropometric, and dietary intake data were collected. Children were studied every 2 weeks for 10 weeks to determine whether they developed kwashiorkor. Dietary intake was assessed on enrollment using a food frequency questionnaire, which included all possible foods in the child's diet. Food frequency data were used to estimate energy, protein, vitamins C and A, niacin, thiamin, zinc, and iron intake using food composition and serving size data. Dietary diversity was assessed with a 7-point score. Regression modeling was used to determine whether the consumption of any food or nutrient was associated with the development of kwashiorkor. RESULTS: A total of 43 (2.6%) of the 1651 healthy children ages 1 to 3 years enrolled developed kwashiorkor. Children who developed kwashiorkor were younger and had more nutritional wasting than those who did not. Thirty children (70%) who developed kwashiorkor were breast-fed. In the combined regression model no foods or nutrients were found to be associated with the development of kwashiorkor. There were no differences in the dietary diversity between children who developed kwashiorkor and those who did not. CONCLUSIONS: No association between the development of kwashiorkor and the consumption of any food or nutrient was found.

Healthy infant with a blistering rash.

The parents denied any environmental exposures and said that the child hadn't had contact with anyone with a similar rash. The distribution of the rash was revealing.

Perifollicular petechiae and easy bruising.

This patient was a liver transplant recipient and had a history of malnutrition. One tell-tale sign on the physical exam, however, left no doubt as to the diagnosis.

Comparison of home-based therapy with ready-to-use therapeutic food with standard therapy in the treatment of malnourished Malawian children: a controlled, clinical effectiveness trial.

BACKGROUND: Childhood malnutrition is common in Malawi, and the standard treatment, which follows international guidelines, results in poor recovery rates. Higher recovery rates have been seen in pilot studies of home-based therapy with ready-to-use therapeutic food (RUTF). OBJECTIVE: The objective was to compare the recovery rates among children with moderate and severe wasting, kwashiorkor, or both receiving either home-based therapy with RUTF or standard inpatient therapy. DESIGN: A controlled, comparative, clinical effectiveness trial was conducted in southern Malawi with 1178 malnourished children. Children were systematically allocated to either standard therapy (186 children) or home-based therapy with RUTF (992 children) according to a stepped wedge design to control for bias introduced by the season of the year. Recovery, defined as reaching a weight-for-height z score > -2, and relapse or death were the primary outcomes. The rate of weight gain and the prevalence of fever, cough, and diarrhea were the secondary outcomes. RESULTS: Children who received home-based therapy with RUTF were more likely to achieve a weight-for-height z score > -2 than were those who received standard therapy (79% compared with 46%; P < 0.001) and were less likely to relapse or die (8.7% compared with 16.7%; P < 0.001). Children who received home-based therapy with RUTF had greater rates of weight gain (3.5 compared with 2.0 g . kg(-1) . d(-1); difference: 1.5; 95% CI: 1.0, 2.0 g . kg(-1) . d(-1)) and a lower prevalence of fever, cough, and diarrhea than did children who received standard therapy. CONCLUSION: Home-based therapy with RUTF is associated with better outcomes for childhood malnutrition than is standard therapy.

Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations.

OBJECTIVE: To determine the prevalence of aquagenic wrinkling of the palms (AWP) in patients with cystic fibrosis (CF) compared with control patients, and evaluate for genotype-phenotype correlations. Since its first description over 30 years ago, AWP has frequently been anecdotally associated with CF, but this association has not been confirmed in a rigorous prospective case-control study. DESIGN: Blinded comparison. SETTING: The CF and dermatology clinics at St Louis Children's Hospital. PARTICIPANTS: Forty-four individuals with CF from a CF clinic and 26 controls from a dermatology clinic. Intervention Participants were tested for AWP using 3 minutes of water immersion with room-temperature tap water. Main Outcome Measure The degree of AWP was scored from 0 (no wrinkling) to 4 (severe wrinkling) by 3 blinded physicians. For genotype-phenotype correlations, patients with CF were divided into those homozygous for the DeltaF508 mutation and those with other genotypes. RESULTS: The mean AWP score of the CF group was significantly higher than the mean score of the control group (1.5 vs 0.6; P < .001). Patients with CF who were homozygous for the DeltaF508 mutation (n = 27) had significantly higher scores than patients with CF who were not homozygous for the DeltaF508 mutation (n = 17) (1.7 vs 1.1; P = .02). The 17 patients with CF who were not homozygous for the DeltaF508 mutation still had higher scores than the control group (1.1 vs 0.6; P = .03). There was no correlation between sweat chloride concentrations measured at the time of diagnosis and AWP score. CONCLUSIONS: Our results confirm the association between AWP and CF. Among patients with CF, greater AWP occurs in those who are homozygous for the DeltaF508 mutation.

Antioxidant supplementation for the prevention of kwashiorkor in Malawian children: randomised, double blind, placebo controlled trial.

OBJECTIVE: To evaluate the efficacy of antioxidant supplementation in preventing kwashiorkor in a population of Malawian children at high risk of developing kwashiorkor. DESIGN: Prospective, double blind, placebo controlled trial randomised by household. SETTING: 8 villages in rural southern Malawi. PARTICIPANTS: 2372 children in 2156 households aged 1-4 years were enrolled; 2332 completed the trial. INTERVENTION: Daily supplementation with an antioxidant powder containing riboflavin, vitamin E, selenium, and N-acetylcysteine in a dose that provided about three times the recommended dietary allowance of each nutrient or placebo for 20 weeks. MAIN OUTCOME MEASURES: The primary outcome was the incidence of oedema. Secondary outcomes were the rates of change for weight and length and the number of days of infectious symptoms. RESULTS: 62 children developed kwashiorkor (defined by the presence of oedema); 39/1184 (3.3%) were in the antioxidant group and 23/1188 (1.9%) were in the placebo group (relative risk 1.70, 95% confidence interval 0.98 to 2.42). The two groups did not differ in rates of weight or height gain. Children who received antioxidant supplementation did not experience less fever, cough, or diarrhoea. CONCLUSIONS: Antioxidant supplementation at the dose provided did not prevent the onset of kwashiorkor. This finding does not support the hypothesis that depletion of vitamin E, selenium, cysteine, or riboflavin has a role in the development of kwashiorkor.