PRKD1-related telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome: Case report and review of the literature.

Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome. We report on the 8th patient carrying a heterozygous de novo variation of PRKD1 c.2134G > A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with PRKD1 missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations. In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.

Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib.

PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability.

Leg amputation and dystrophic epidermolysis bullosa: A case report with 15 years of follow-up.

OBJECTIVE: Dystrophic epidermolysis bullosa is a rare disease characterized by widespread blistering of the skin and mucous membranes, which may ultimately prompt limb amputation. In this context, the outcome of fitting a prosthesis to a chronically wounded stump is not well known. Our patient's experience (with 15 years of follow-up) should contribute to better knowledge of this topic. CASE REPORT: A 37-year-old man presented with severe dystrophic epidermolysis bullosa. Recurrent skin carcinoma had led to an amputation below the knee. Despite incessant development of blisters on the stump and the need for wound dressing and padding, the patient has been able to walk freely with a prosthesis and a cane. A large number of skin sarcomas were excised over the 15-year period of prosthesis use. Two falls have resulted in limb fractures. A new sarcoma on the stump marked the end of the use of the prosthesis. DISCUSSION: Despite the constant presence of wounds on the stump, amputees with dystrophic epidermolysis bullosa can successfully be fitted with a prosthesis.

Skin Patterns Associated with Upper Airway Infantile Haemangiomas: A Retrospective Multicentre Study.

The aim of this study was to define the skin patterns at high risk for upper airway infantile haemangioma. A retrospective multicentre French observational study was conducted between January 2006 and January 2015 and all confirmed airway haemangioma were included. Thirty-eight patients with airway haemangioma from 9 centres were included. Thirty-one patients had a cutaneous or mucosal haemangioma: 21 with a location considered at high risk for airway haemangioma (large segmental mandibular haemangioma), 4 with a very mild facial involvement (lower lip or S1 (frontotemporal segment according to Haggstrom and Frieden)) and 6 with either lesions of the neck or body, or association of both. We report here the largest cohort of airway haemangioma. A third of patients do not completely fit with the definition of the high-risk area of airway haemangioma. Segmental lower lip and neck involvement also seem to be very suggestive areas. Clinicians must be able to recognize these areas.

Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis.

Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations.

Adult mastocytosis is an incurable clonal disease associated with c-KIT mutations, mostly in exon 17 (D816V). In contrast, pediatric mastocytosis often spontaneously regresses and is considered a reactive disease. Previous studies on childhood mastocytosis assessed only a few patients and focused primarily on codon 816 mutations, with various results. In this study, we analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis (ages 0-16 years). A mutation of codon 816 (exon 17) was found in 42% of cases, and mutations outside exon 17 were observed in 44%. Unexpectedly, half of the mutations were located in the fifth Ig loop of c-KIT's extracellular domain, which is encoded by exons 8 and 9. All mutations identified in this study were somatic and caused a constitutive activation of c-KIT. There was no clear phenotype-genotype correlation, no clear relationship between the mutations and familial versus spontaneous disease, and no significant change in the relative expression of the c-KIT GNNK+ and GNNK isoforms. These findings strongly support the idea that, although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with activating mutations in c-KIT.

Neurocutaneous melanosis and the Dandy-Walker complex: an uncommon but not so insignificant association.

BACKGROUND: Neurocutaneous melanosis represents a rare congenital but nonheritable phakomatosis defined as the association of giant or multiple congenital nonmalignant melanocytic nevi with leptomeningeal melanosis or melanoma of the central nervous system. METHODS: We describe the case of an adolescent with a giant congenital bathing trunk melanocytic nevus who developed progressive intracranial hypertension due to leptomeningeal melanosis confirmed by surgical biopsy. Brain and spine magnetic resonance images showed posterior fossa malformation compatible with the Dandy-Walker complex, hydrocephalus, and extensive enhancement of posterior fossa then spine. Shunt placement, corticotherapy, and chemotherapy were attempted leading to transient relief but the boy died 12 months after the onset of primary neurological symptoms. DISCUSSION: We discuss diagnosis, pathogenesis, management, and prognosis in the light of data from the recent literature. CONCLUSION: Neurocutaneous melanosis is considered to follow from neurulation disorders which could account for associated developmental malformations as the so-called Dandy-Walker complex. Cutaneous lesions are usually recognized at birth whereas neurological manifestations develop later. Numerous neurological symptoms have been reported according to extent of leptomeningeal and parenchymal infiltration. Whether magnetic resonance imaging of the neuroaxis represents the choice radiological exam, definite diagnosis relies upon the histological data obtained by mean of biopsy. Once symptomatic, surgical and medical measures remain palliative since death occurs within 3 years.

Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease.

Imatinib is a promising candidate for the treatment of fibrotic diseases. This retrospective study evaluated the use of imatinib for the treatment of refractory sclerotic chronic graft-versus-host disease in 14 patients with different hematologic malignancies. Imatinib was started at a median of 44 months after transplantation (range, 16-119 months after transplantation) and was administered for a median of 5.9 months from time of initiation (range, 2.1-74 months from time of initiation). With a median overall follow-up of 11.6 months from time of initiation (range, 4.1-74 months from time of initiation) of imatinib, 4 patients (29%) had to stop imatinib because of drug intolerance. All other adverse reactions were of mild-to-moderate grade and could be managed symptomatically. Overall, 7 patients responded to imatinib (50%; 95% confidence interval, 24%-76%) with 4 patients improving their Rodman score more than or equal to 90%. In addition, imatinib therapy allowed for a significant reduction of corticosteroid dosage. Despite its limited size, this cohort suggests some beneficial activity of imatinib in sclerotic chronic graft-versus-host disease, warranting further prospective investigations.

Conversion to sirolimus: a useful strategy for recalcitrant cutaneous viral warts in liver transplant recipient.

Dermatological complications following transplantation are very common and the majority of immunosuppressed transplant recipients develop some to many warts due to human papillomavirus (HPV) infection. In the setting of immunosuppression, therapeutic management may be disappointing because of the extent of the lesions in patients unable to develop a sufficient immune response directed against HPV. We report here a case of a young liver transplant recipient who developed diffuse recalcitrant HPV-induced warts leading to an impairment of her quality of life. Taking into account the antiproliferative and cytostatic properties of the target-of-rapamycin (TOR) inhibitors, a new class of immunosuppressive drug, we significantly modified the immunosuppressive regimen. Conversion to sirolimus was followed by a rapid improvement of cutaneous state suggesting that this strategy may be useful for recalcitrant cutaneous viral warts in transplant recipient.

Successful outcome of disseminated Fusarium infection with skin localization treated with voriconazole and amphotericin B-lipid complex in a patient with acute leukemia.

A disseminated Fusarium oxysporum infection with skin localization was diagnosed in a woman with a relapse of B-acute leukemia during induction chemotherapy. The infection was refractory to amphotericin B-lipid complex alone but responded successfully when voriconazole was added.

Congenital elephantiasis-like lymphangiomatosis of a lower limb.

The case of a newborn girl with a rare, giant, congenital, tissue lymphangioma giving rise to elephantiasis of the right lower limb is presented. The different imaging methods, especially magnetic resonance imaging, showed no extension of the lesions into the deep structures. At the age of 2 years, the child underwent a roentgenographic skeletal survey, which revealed osteolytic lesions in the femurs and the right tibia. There was no clinical evidence of systemic involvement. The place of this affection among the different lymphatic malformations was discussed and the diagnosis of elephantiasis-like lymphangiomatosis of the limb, an extremely rare disorder, has been retained. Early surgical reduction was performed, followed by application of a pressure dressing. Five years later the result remains satisfactory, but the excision of a persistent fluid-filled pouch around the knee will probably be necessary in the future.