Shari R. Lipner, MD, PhD

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹