ß-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA.

ß-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme ß-mannosidase. The disease is caused by mutations in MANBA and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. We report a 15-yr-old girl presenting with mild intellectual disability, sensorineural hearing loss, severe behavioral disturbances, dysmorphic traits, and evolving angiokeratomas. Copy-number variation analysis of next-generation sequencing (NGS) data indicated increased coverage in exons 8-11 of MANBA Low ß-mannosidase activity (1 µkatal/kg protein, refv 25-40) established the diagnosis of ß-mannosidosis. Whole-genome sequencing (WGS) and cDNA analysis revealed a novel homozygous intragenic inverted duplication in MANBA, where a 13.1-kb region between introns 7 and 11 was duplicated and inserted in an inverted orientation, creating a 67-base nonduplicated gap at the insertion point. Both junctions showed microhomology regions. The inverted duplication resulted in exon skipping of exons 8-9 or 8-10. Our report highlights the importance of copy-number variation analysis of data from NGS and in particular the power of WGS in the identification and characterization of copy-number variants.

Transcriptomic analysis of FUCA1 knock-down in keratinocytes reveals new insights into the pathogenesis of fucosidosis skin lesions.

Fucosidosis is a rare lysosomal storage disease which has been classified into two subtypes, depending on the severity of clinical signs and symptoms. Fucosidosis patients' skin abnormalities include angiokeratoma corporis diffusum, widespread telangiectasia, thick skin, hyperhidrosis and hypohidrosis, acrocyanosis and distal transverse nail bands. It has been described that >50% of fucosidosis patients have angiokeratoma. At molecular level, fucosidosis is caused by lysosomal alpha-L-fucosidase (FUCA1) gene mutations. Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. The effect of FUCA1 dysfunction on gene expression is unknown. The aim of this study was to analyse, in keratinocytes, the transcriptomic effect of FUCA1 knock-down for a better understanding of skin lesions' pathogenesis affecting fucosidosis patients. FUCA1 knock-down (siRNA) was performed in human HaCaT immortalised keratinocytes. Affymetrix arrays and qPCR were used for analysing gene expression. Bioinformatics was used for functional clustering of modified genes. In total, 387 genes showed differential expression between FUCA1 silenced and non-silenced cells (222 up-regulated and 165 down-regulated). Up-regulated genes belonged to two major groups: keratinocyte differentiation/epidermal development (n = 17) and immune response (n = 61). Several transcription factors were up-regulated in FUCA1-siRNA transfected cells. This effect might partly have been produced by abnormal transcription factor expression, that is FOXN1. We thus propose that fucosidosis-related skin lesions (eg angiokeratoma) and those of other diseases (eg psoriasis) might be caused by dysfunctions in common aetiological overlapping molecular cascades.

Cerebral cavernous malformations associated with cutaneous angiokeratomas and hemangiomas.

We report the case of a 66-year-old man with adult-onset seizures and multiple cerebral cavernous malformations who developed numerous eruptive cutaneous angiokeratomas on the legs, scrotum, abdomen, and back as well as lobular and cavernous hemangiomas on the arms. Genetic analysis demonstrated a mutation in the KRIT1, ankyrin repeat containing gene (also known as CCM1).

Fabry disease: clinical and genotypic aspects of three cases in first degree relatives.

Fabry disease is an X-linked, lysosomal storage disease caused by the inherited deficiency of the enzyme α-galactosidase A. The diagnosis is usually late, with renal, cardiovascular and/or cerebral complications that reduce life expectancy. Angiokeratomas are asymptomatic lesions present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of treatment with enzyme replacement therapy, which prevents late complications reducing morbidity and mortality. We report a case of a male teenager with acroparestesias and angiokeratomas. Family medical research discovered that his mother and brother had similar signs and symptoms and that the three patients had the same mutation in the gene encoding the enzyme, confirming the diagnosis.

Fabry disease: clinical and genotypic aspects of three cases in first degree relatives

Fabry disease is an X-linked, lysosomal storage disease caused by the inherited deficiency of the enzyme α-galactosidase A. The diagnosis is usually late, with renal, cardiovascular and/or cerebral complications that reduce life expectancy. Angiokeratomas are asymptomatic lesions present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of treatment with enzyme replacement therapy, which prevents late complications reducing morbidity and mortality. We report a case of a male teenager with acroparestesias and angiokeratomas. Family medical research discovered that his mother and brother had similar signs and symptoms and that the three patients had the same mutation in the gene encoding the enzyme, confirming the diagnosis.

Angiokeratomas - When is a few too many?

Many patients have a few scattered angiokeratoma and we reassure them that this it is normal; however, if they are numerous, Fabry disease should be considered and the family history should be checked.

[A new location of angiokeratoma circumscriptum]. / Une nouvelle localisation de l'angiokératome circonscrit næviforme.

BACKGROUND: Angiokeratomas are papular telangiectasias having a common histology of ectasia of the superficial dermal vessels surmounted by a hyperkeratotic epidermis. PATIENTS AND METHODS: The patient was a 9-year-old girl born of non-consanguineous parents after a well-followed pregnancy with problem-free delivery at term. From birth, she had a tumefaction of the left side of the nose and the left half of the upper lip that gradually increased in size without obstructing the nasal orifice and bled easily. Examination revealed the presence of tumefaction of the left nostril and the left half of the upper lip projecting towards the contralateral side especially in the nose. It was soft and painless, with the presence at the surface of dull red keratotic papules of 1 to 2 mm in diameter. Examination of the nasal mucosa revealed the same appearance of papules. DISCUSSION: Angiokeratoma circumscriptum is a rare congenital malformation, the rarest of five types. Since its initial description in 1890, few cases have been reported. However, female predominance has been noted with a male/female sex ratio of 1/3. It appears to be due to a genetic mutation that is probably autosomal, but the site of which is still unknown. In view of the special features of this case, several diagnoses were suggested, including Rendu Osler's disease, superficial lymphangioma and verrucous angioma. CONCLUSION: The particularity of this case is that it includes the first description of this site, which posed a therapeutic problem, especially concerning the choice of laser type to be used.

A family with Fabry disease diagnosed by a single angiokeratoma.

This case presents a 39-year-old gentleman with a single angiokeratoma on the abdomen. Because of a family history of early onset cardiac disease, testing for Fabry disease was performed and a mis-sense mutation (A143T) in the Fabry gene confirmed the diagnosis. The unusual aspect of this case is that the patient otherwise had normal health. His only detectable abnormality was a high serum creatinine at 116 mmol/L. Two further affected males and four carrier females were detected on family screening. We tested a further five patients with a single angiokeratoma for Fabry disease. In the five tested though, no suggestive personal or family history was given for any of the patients and no further cases were detected. This case highlights the need for vigilance within dermatology clinics to consider Fabry disease even if a solitary angiokeratoma is the only presenting feature. Some patients do display a milder phenotype and thus a detailed family history should always be taken. As in this case, a solitary angiokeratoma and a suspicious family history may be the only clue. Because enzyme replacement therapy is now available, the potential benefits for the patient and their family are high.

A case of multiple angiomas without any angiokeratomas in a female heterozygote with Fabry disease.

Fabry disease is a rare, X-chromosome-linked lysosomal storage disease caused by a deficient alpha-galactosidase A enzyme. The disease manifests primarily in affected hemizygous males and to some extent in heterozygous females ('carrier'). A 45-year-old female Fabry disease patient without angiokeratomas but with numerous angiomas is presented. Her leukocyte alpha-galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4-1). The analysis of her alpha-galactosidase A gene (exon 1-7) showed the transition c.427 G>A. An intrafamilial follow-up search detected a reduced leukocyte alpha-galactosidase A activity in her father, who suffered exclusively from coronary heart disease. Our case report underlines the possible wide range of clinical signs in Fabry disease patients, sometimes complicated by missing typical lesions (e.g. angiokeratomas). In oligosymptomatic Fabry disease cases, genetic analysis is recommended.

Angiokeratoma: a cutaneous marker of Fabry's disease.

The initial symptoms of Fabry's disease (FD) may seem harmless and may delay its diagnosis. A survey and screening for FD were performed on men with biopsy-proven angiokeratoma and some of their relatives (n = 29). Three patients were identified. Dermatologists should be aware of this prominent early feature and investigate unexplained cutaneous vascular lesions to detect FD.

Angiokeratoma circumscriptum arranged in a systematized band-like pattern suggesting mosaicism.

A 10-year-old girl with vascular lesions that had been present since birth is reported. Initially, small red macules were limited to the legs, but later the lesions became more extensive. A hyperkeratotic aspect of the lesional skin surface had developed at the age of 2 years. On clinical examination, hyperkeratotic vascular lesions in a band-like distribution on the trunk, legs and face were observed. The type of lesion varied from discrete macules with no or slight hyperkeratosis to confluent, protruding verrucous plaques. The clinical and histopathological findings were consistent with a diagnosis of angiokeratoma circumscriptum. The systematized band-like arrangement observed in the present case strongly supports the concept that angiokeratoma circumscriptum reflects a mosaic state of a mutation that is so far unknown.

Acral pseudolymphomatous angiokeratoma of children: immunohistochemical and clonal analyses of the infiltrating cells.

BACKGROUND: Acral pseudolymphomatous angiokeratoma of children (APACHE) is a disorder characterized clinically by red nodules and histopathologically by a massive subepidermal lymphohistiocytic infiltrate. Although it was initially thought to be a vascular nevus, it has never been regarded as a pseudolymphoma. CASE REPORT: We report a 7-year-old-girl with small red nodules on the dorsum of the right foot and a 73-year-old man with asymptomatic brown-red nodules on the lower extremities. RESULTS: Histopathologic examination revealed a massive lymphohistiocytic infiltrate with plasma cells, some eosinophils, or a multinucleated giant cell immediately beneath the epidermis. Thick-walled vessels were observed in the infiltrate. These characteristics are identical to those of acral pseudolymphomatous angiokeratoma of children. The infiltrate was composed mainly of equal numbers of CD4+ or CD8+ T cells and equal numbers of B cells stained for kappa or lambda light chains. PCR amplification of rearranged immunoglobulin heavy chain genes or T-cell receptor gamma genes showed no evidence of clonality, suggesting that these infiltrates were polyclonal both for B and T cells. CONCLUSIONS: Our data support the idea that this disorder represents a reactive process. The modified term 'papular angiolymphoid hyperplasia' would define this disorder more appropriately.

Ramon syndrome with diabetes mellitus and vascular skin lesions in two sibs.

Two sibs are reported with Ramon syndrome with the previously undescribed associations of insulin dependent diabetes mellitus and vascular skin lesions.

Two Japanese cases with aspartylglycosaminuria: clinical and morphological features.

Two members of a consanguineous Japanese family with a clinical picture of aspartylglycosaminuria (AGU) are described. Both patients exhibited mental retardation, coarse facial features, angiokeratoma and myoclonic seizures. Biochemical studies showed elevated excretion of urinary sialyloligosaccharides and decreased activity of aspartylglycosaminidase in lymphoblasts. Morphologic studies of skin biopsy specimens showed many clear vacuoles mainly in the vascular endothelial cells and secretory cells of the sweat glands. Osmiophilic lamellar cytoplasmic inclusions were also noted in the ganglion cells in rectal biopsy. The ethnic distribution of AGU may be more widespread than previously suspected and appears not to be restricted to Finnish populations. Ours are the first Japanese patients diagnosed as AGU. We conclude that AGU should also be included in the differential diagnosis of mentally retarded patients in Asian countries.