The term acral coldness is used to describe physiologic or pathologic situations in humans where the fingers and toes are exceptionally cold in spite of normal central body temperature. In the thermoneutral zone, the blood flow to acral skin normally shows large fluctuations between high and low values, with a frequency of about 3 cycles per minute. At an acral skin temperature of about 21°C, finger blood flow is constantly low. At lower temperatures the fingers and toes become painful. This is a normal physiologic reaction, probably because of ischemia. The characteristics of the most frequent acral vascular syndromes, Raynaud phenomenon, acrocyanosis, and chilblains, are discussed. Common to all three is pathologically low blood flow and disappearance of physiologic fluctuations even in the thermoneutral zone. Ischemic vascular diseases in acral skin are usually diagnosed from clinical observations. Measurements of fluctuating blood flow by laser or ultrasound Doppler could be useful, but should be carried out at a room temperature of 24-25°C.

Amphetamine and its related derivatives and analogues (ADRA) are highly addictive central nervous system stimulants that are used commonly in the treatment of attention-deficit/hyperactivity disorder and narcolepsy. These medications are associated with many side effects but reports of peripheral arterial manifestations associated with ADRA usage are scarce. We retrospectively reviewed the records of 16 patients (median age 37 years (IQR 31-47), 13 females) referred to a single tertiary referral service while receiving ADRA. Follow-up was available for a median of 3 years (IQR 3-4.5). The most common presentation (62.5%) was mild vasospastic symptoms involving the upper, lower or both extremities. Six patients developed severe manifestations including tissue loss and the need for lower extremity amputation. Most patients (75%) refused to stop the medication during follow-up. Underlying rheumatologic disorders were found in 25% of the patients, and the presence of rheumatologic disease seemed to be associated with more severe vascular manifestations. In conclusion, it is important to search for ADRA usage as part of the differential diagnosis of digital ischemia.

In the contemporary era of medical diagnosis via sophisticated radiographic imaging and/or comprehensive serological testing, a focused physical examination remains paramount in recognizing the cutaneous manifestations of chronic vascular disease. Recognition of the unique cutaneous signs of lymphatic and venous hypertension assists in the diagnosis as well as the staging and classification of both lymphedema and chronic venous insufficiency. Awareness of explicit dermatologic vasomotor manifestations aids not only in the identification of acrocyanosis, Raynaud phenomenon, pernio, and erythromelalgia but also mitigates confusion related to their clinical overlap. Although the clinical signs of peripheral artery disease are not necessarily specific or sensitive, a knowledge of suggestive dermatologic findings is helpful in recognition of severe limb ischemia. A brief review of the epidemiology, etiology, pathogenesis, and therapy of cutaneous related chronic vascular disease follows including an emphasis on characteristic clinical features supported by illustrative photographs.

Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix® Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers.

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.