Pediatric Raynaud Phenomenon

Updated: Sep 01, 2016
  • Author: Suzanne C Li, MD, PhD; Chief Editor: Lawrence K Jung, MD  more...
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Overview

Background

Raynaud phenomenon (RP) was first described by Maurice Raynaud in 1862 and refers to a transient vasospasm of peripheral arteries and arterioles that classically results in triphasic color changes in the affected region. [1, 2, 3, 4] The initial artery and arteriole vasospasm causes pallor (white), followed by cyanosis (blue) due to dilation of the capillaries and venous stasis (deoxygenated blood), with continued artery and arteriole vasospasm. The arteries and arterioles then dilate, causing rapid return of blood flow (red, reactive hyperemia). [1, 2, 5] The fingers are the most commonly affected region, and Raynaud phenomenon is typically triggered by cold exposure or stress. [2, 6, 7, 8]

See the image below.

Raynaud phenomenon showing demarcation of color di Raynaud phenomenon showing demarcation of color difference.

Raynaud phenomenon can be primary (idiopathic), meaning no associated diseases are present (about 80-90% of cases), or secondary, meaning that another condition is believed to be the cause of the Raynaud phenomenon. [2, 9, 10] Connective tissue diseases are the most common cause of secondary Raynaud phenomenon, but several medications and many other conditions are also associated with Raynaud phenomenon. [11, 12, 13]

In the past, Raynaud phenomenon had been referred to as Raynaud syndrome, with Raynaud disease referring to primary Raynaud phenomenon, and Raynaud phenomenon referring to secondary Raynaud phenomenon; however, these terms were often used interchangeably. [14, 15, 2] The current preferred terminology of primary and secondary Raynaud phenomenon was proposed by LeRoy and Medsger in 1992. [16] Primary Raynaud phenomenon rarely leads to significant problems and does not usually need to be treated with medications. In contrast, secondary Raynaud phenomenon, especially when associated with scleroderma-related diseases, often causes irreversible digital ischemia, resulting in the development of digital ulcers or even digital amputation. [2, 6, 9]

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Pathophysiology

The pathophysiology of Raynaud phenomenon is not completely understood; the vasospasm that occurs in the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts involves both central and peripheral mechanisms. [2, 4, 12, 17, 18] The pathophysiology of secondary Raynaud phenomenon also involves structural changes to the vasculature that worsens the severity of the Raynaud phenomenon.

Raynaud phenomenon can be thought of as an exaggerated normal response to cold and emotional stress. [9, 19] The skin of the digits is supplied by both thermoregulatory and nutritional blood flow. Blood flow to the skin is decreased in response to cold environmental temperatures and is increased in response to warm temperatures. [5] This thermoregulation is controlled by the sympathetic nervous system, which regulates flow through the arteriovenous shunts. [5] In contrast, nutritive flow is constant and is supplied by a capillary network. [5]

Primary Raynaud phenomenon rarely affects the nutritive flow, whereas secondary Raynaud phenomenon can cause digital artery vasospasm severe enough to block the nutritive flow, leading to tissue hypoxia and ischemia. [5] Patients with Raynaud phenomenon have a decrease in digital blood flow rates and a longer lag time before peak blood flow returns following cold exposure compared with normal controls; patients with secondary Raynaud phenomenon have a greater defect than patients with primary Raynaud phenomenon. [2, 17, 12] Patients with Raynaud phenomenon have a defective pattern of flow in response to digit cooling. [18]

Structural vascular defects in patients with secondary Raynaud phenomenon who have systemic sclerosis include endothelial cell apoptosis (due to repeated ischemia and antiendothelial cell antibodies), upregulation of adhesion molecules, formation of fibrous intimal lesions, intimal proliferation, capillary enlargement and atrophy, obliteration of vessel patency by perivascular fibrosis or thrombus formation, and defective vascular remodeling and arteriogenesis. [20, 5, 21, 12, 4]

Functional vascular defects include impaired endothelial-dependent vasodilation, decreased production of vasodilator substances (increased production of endothelial nitric oxide synthetase inhibitor), and increased production of vasoconstrictors such as endothelin-1 and angiotensin II in systemic sclerosis patients. [4, 12]

A study that assessed microcapillary status and serum concentrations of chosen cytokines, adhesive molecules, and nitric oxide in pediatric patients with primary Raynaud syndrome and secondary Raynaud syndrome found that external factor-induced vasoconstrictive effects dominated in primary Raynaud syndrome, whereas in secondary Raynaud syndrome in the course of connective tissue diseases, it was accompanied by coexistent vasodilation due to endothelial dysfunction which was partially dependent on insufficient nitric oxide release. [22]

Raynaud phenomenon patients also show impairments in neural regulation of vascular tone. Both primary Raynaud phenomenon and secondary Raynaud phenomenon patients have decreased levels of calcitonin gene–related peptide (CGRP), a potent vasodilator released from sensory afferents. [12] The level of vasodilator vasoactive intestinal peptide has also been found to be lower in Raynaud phenomenon patients. [4] Systemic sclerosis patients have increased levels of one of the adrenergic a2 receptor subtypes in skin arterioles, which leads to increased reactivity and vasoconstriction in response to cold. [4, 12]

Intravascular defects associated with Raynaud phenomenon include the following [4, 12, 23] :

  • Platelet activation - Present in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to increased levels of the vasoconstrictors thromboxane A2 and serotonin and other substances that can contribute to inflammation or angiogenesis such as platelet microparticles and platelet-derived growth factor
  • Defective fibrinolysis - Found in patients with secondary Raynaud phenomenon; can lead to fibrin deposition and obstruction of vasculature
  • WBC activation - Found in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to damage from oxidative stress
  • Decreased RBC deformability - Found in secondary Raynaud phenomenon; can lead to impairment of blood flow
  • Increased blood viscosity - Found in both primary Raynaud phenomenon and secondary Raynaud phenomenon; can lead to impaired blood flow
  • Oxidative stress - Triggered by ischemic episodes; decreased levels of antioxidants found in both primary Raynaud phenomenon and secondary Raynaud phenomenon (Free radicals can trigger neutrophil activation, and oxidative stress can lead to further endothelial damage.) [24]

Raynaud phenomenon is thought to be a polygenic phenomenon. About one fourth of patients with primary Raynaud phenomenon have a family history of Raynaud phenomenon in a first-degree relative; secondary Raynaud phenomenon also occurs more frequently in families with a history of Raynaud phenomenon or connective tissue disease. [2] Raynaud phenomenon is also known to be associated with migraine headaches; recently, a genetic locus for migraines and Raynaud phenomenon, 3p21.1-p21.3, was identified in a Dutch family. [25] A genome screen in 6 extended families with multiple cases of Raynaud phenomenon identified 3 potential genes associated with primary Raynaud phenomenon. [26]

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Epidemiology

Frequency

Only one pediatric study has been done to assess the prevalence of pediatric Raynaud phenomenon. Jones et al surveyed 720 British school children aged 12-15 years to determine the prevalence of Raynaud phenomenon and its association with other problems. [27] Surveys containing color pictures were shown to the students who were asked to identify which picture corresponded with their digit color during episodes of cold sensitivity. The students were required to identify a distinct demarcation of color difference and the presence of digital pallor. The students also had to answer affirmatively to the following questions: [27]

  • “Do your fingers change color in cold at least once per month?”
  • “Have your fingers become numb or felt tingly or like pins and needles in the cold?”

The overall prevalence was 14.9%; an 18% prevalence was reported in the girls, and a 12% prevalence was reported in the boys. [27] Prevalence increased with age, especially in girls (9.8-14.3% in boys; 11.4-44% in girls). [27]

A review of Raynaud phenomenon from 10 international sites reported that 2.2% of 1247 patients had onset of primary Raynaud phenomenon within the first decade of life, and 19.9% had onset within the second decade of life (2.8-55.6% range for onset within the first 2 decades of life). [28]

The pediatric prevalence is similar to that reported in adults. Overall adult prevalence ranges from 3-20%, with higher rates found in females than in males, and higher rates found in colder climates. [29] A prospective community-based adult study found an incidence of Raynaud phenomenon of 2.2% for females and 1.5% for males, and a prevalence of 11% for middle aged women and 8% for middle aged men. [30]

In a review of outpatient clinic and hospital admission records, 69% of pediatric patients had primary Raynaud phenomenon, and 28% had secondary Raynaud phenomenon. [6] One study of 250 pediatric patients with Raynaud phenomenon (mean age, 15 y) reported 76% of patients had primary Raynaud phenomenon and 24% had secondary Raynaud phenomenon. [31] An additional study of 27 pediatric patients with Raynaud phenomenon reported 33% of patients had primary Raynaud phenomenon, 15% had probable secondary Raynaud phenomenon, and 52% had secondary Raynaud phenomenon. [15]

The frequency of Raynaud phenomenon in patients with different connective tissue diseases is as follows:

Adult patients with rheumatoid arthritis were reported to have a 20% prevalence of Raynaud phenomenon, and adult patients with Sjögren syndrome had a 13% prevalence of Raynaud phenomenon. [9]

Mortality/Morbidity

Morbidity is related to the severity and duration of the Raynaud phenomenon episode. When pallor is present, ischemia is more likely than cyanosis; no ischemia is associated with the reactive hyperemia phase. Severe pain suggests that the vasospasm is affecting nutritional flow. [5] Although patients with primary Raynaud phenomenon do not usually experience significant morbidity due to Raynaud phenomenon, pediatric studies have reported digital ulcers and even gangrene. [37, 14, 6] Patients with limited systemic sclerosis or calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias (CREST) syndrome are at greater risk for digital ischemia than those with diffuse systemic sclerosis; 20% of patients with limited systemic sclerosis have been reported to lose at least one digit due to Raynaud phenomenon. [2]

Morbidity in patients with Raynaud phenomenon syndrome includes the following:

  • Altered sensation: Paresthesia, numbness, and pain were reported in as many as 67% of pediatric patients with primary Raynaud phenomenon and 63% of those with pediatric secondary Raynaud phenomenon. [6]
  • Digital pits: A shallow divot in the tip of the digit due to ischemia is found in 2% of pediatric patients with primary Raynaud phenomenon and 15% of pediatric patients with secondary Raynaud phenomenon. [6]
  • Digital ulcerations: A deeper and more extensive loss of tissue on the digit tip due to ischemia is found in 5% of pediatric patients with primary Raynaud phenomenon and 18% of pediatric patients with secondary Raynaud phenomenon. [38] Digital ulcers have been reported in 30-50% of adult patients with scleroderma. [33]
  • Poor wound healing in digits: In pediatric patients with primary Raynaud phenomenon, the prevalence of poor wound healing in digits was 2%; in pediatric patients with secondary Raynaud phenomenon, a prevalence of 6% was reported. [6]
  • Digital gangrene: Severe ischemia results in tissue necrosis with gangrene; self-amputation may occur or surgical debridement may be needed. Digital gangrene is reported in 3% of pediatric patients with secondary Raynaud phenomenon and was not reported in pediatric patients with primary Raynaud phenomenon in the largest pediatric series. [6] Early studies reported of pediatric patients with primary Raynaud phenomenon who developed digital gangrene; however, the authors did not comment on nailfold capillary examination. Therefore, some of these patients may have represented slowly evolving secondary Raynaud phenomenon. [14, 37]
  • Hospitalization for Raynaud phenomenon due to need for more intensive treatment: One percent of pediatric patients with primary Raynaud phenomenon are hospitalized for intensive treatment, and 6% of pediatric patients with secondary Raynaud phenomenon are hospitalized for intensive treatment. [38]

A higher frequency of morbidity (eg, digital ulcers, need for hospitalization) was reported in patients with primary Raynaud phenomenon who had antiphospholipid antibodies. [6]

Mortality related to Raynaud phenomenon has not been reported in pediatric patients. Severe Raynaud phenomenon is an indicator of a serious and potentially fatal underlying disease. In adult patients with mixed connective tissue disease, severe Raynaud phenomenon is associated with a higher mortality rate, [39] whereas late onset of Raynaud phenomenon in adult patients with scleroderma is associated with an increased prevalence of renal and lung disease. [40]

Cold-induced vasospasm of blood vessels in other organs, including the lungs, heart, GI tract, cerebral vascular system, and kidneys, has also been reported in adults. [41, 42, 18] One adult patient had severe dyspnea related to a coronary artery vasospasm that caused left ventricular heart dysfunction; his symptoms resolved with treatment using a prostacyclin analogue (iloprost). [43] Another patient had improvement in his left ventricular dyskinesia with nifedipine treatment. [41] Cold-induced vasospasm of heart (cardiac Raynaud phenomenon) was found to be a predictor for development of systolic left ventricular dysfunction in systemic sclerosis patients. [44]

Race

Few studies have examined racial predominance in Raynaud phenomenon; Raynaud phenomenon has been reported worldwide, with no reported racial difference. [29] In one pediatric study of 27 patients, patients with primary Raynaud phenomenon were predominantly white, whereas no racial predominance was seen in patients with secondary Raynaud phenomenon. [15]

Sex

Females are more commonly affected than males. Most studies report a female-to-male ratio of 3-4:1. [15, 6, 31] No difference has been reported in the female-to-male ratio of primary Raynaud phenomenon and secondary Raynaud phenomenon incidence. [15, 6, 31]

Adult studies generally report a female-to-male ratio of 2-4:1. Some studies have reported a higher prevalence in males than in females, but this is believed to reflect secondary disease related to vibration or other occupational trauma; when these patients are excluded, females with Raynaud phenomenon greatly outnumber males with Raynaud phenomenon. [45]

The prevalence of Raynaud phenomenon in adult males and females in different countries is as follows:

  • United States - 4.3% in females, 2.7% in males; [28] 11% in females, 8% in males [30]
  • United Kingdom - 19% in females, 11% in males [46]
  • Italy - 3.4% in females, 0.5% in males [47]
  • Hungary - 5.3% in females, 7.7% in males [48]
  • Japan - 2.5% in females, 3.3% in males [28]

Age

Two pediatric studies reported a similar mean age of onset. Nigrovic et al reported primary Raynaud phenomenon had a mean age of onset of 12.2 (± 4.3) years, whereas secondary Raynaud phenomenon had a mean age of onset of 12.7 (± 4.4) years, with a range of 1-19 years. [38] Duffy et al reported a mean age of onset for their mixed population of patients with primary Raynaud phenomenon and Raynaud phenomenon of 11.7 years, with a range of 1.8-17.6 years. [15]

Adult studies have reported that Raynaud phenomenon starts at a younger age in colder regions than in warmer regions; 42.3% of patients with Raynaud phenomenon had onset at younger than 20 years in the coldest region studied compared with 20.4% of patients in warmer locations. [49, 29] A younger age of onset (< 20 y) was reported to be more common in patients with primary Raynaud phenomenon than in those with secondary Raynaud phenomenon, but a large overlap in ages was noted between these 2 groups; these authors reported that reactive hyperemia at the end of attack and discoloration of the earlobes and nose were also more likely to be associated with primary Raynaud phenomenon than with secondary Raynaud phenomenon. [50]

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