Disorders Due to Physical Agents

Caroline A. Nelson, MD

Photodermatoses

Basic Concepts

Abnormal cutaneous effects of UVR exposure may be classified as idiopathic photodermatoses, defective DNA repair and chromosomal instability disorders, photoaggravated dermatoses, and chemical- and drug-induced photosensitivity (endogenous or exogenous).
Normal cutaneous effects of UVR exposure may be acute/subacute or chronic.
Evaluation of photodermatoses often includes:
- Phototesting: use of a solar simulator (eg, an optically filtered xenon arc lamp) to calculate MEDs to UVB, UVA, and visible light.
- Photoprovocation testing: exposure of one forearm to UVB light and one forearm to UVA light daily for 3 days.
- Photopatch testing: placement of duplicate sets of photoallergens on the back followed by exposure of one set to UVA light.

POLYMORPHOUS LIGHT ERUPTION

→ Diagnosis Group 2

Epidemiology

Polymorphous light eruption (PMLE) is the most common idiopathic photodermatosis. The hypothesized pathogenesis is a delayed-type, cell-mediated (type IV) reaction to endogenous cutaneous photoinduced antigens.
Prevalence is inversely related to latitude (highest in Scandinavia). Incidence peaks in the second and third decades and there is a female predominance. PMLE is most severe during the spring and summer.
- The term “hardening” refers to UVR-induced immunologic tolerance, which is likely responsible for the low prevalence of PMLE at the Equator.
UVB > UVA > visible light are triggers.
- Juvenile spring eruption is a PMLE variant in children, especially boys.
- Actinic prurigo is a PMLE variant primarily in Native Americans. Incidence peaks in the first decade and there is a female predominance. Actinic prurigo is most severe during the spring and summer but may persist year-round. It is often familial, with HLA associations including -DR4 (DRB1*0401) and subtype DRB1*0407.

Clinicopathological Features

PMLE classically presents with pruritic erythematous papules, papulovesicles, vesicles, or plaques in sun-exposed areas within hours after light exposure. The face and other sites exposed year-round may be spared. Lesions heal without scarring.
- Juvenile spring eruption is characterized by vesicles favoring the ear helices.
- Actinic prurigo is characterized by pruritic erythematous papules or nodules ± hemorrhagic crusts in both sun-exposed and covered areas. Lesions heal with scarring. Cheilitis ± conjunctivitis is common.
- Figure 4.1.

Evaluation

The differential diagnosis of PMLE includes other photodermatoses and LE.
Skin biopsy may be helpful to diagnose PMLE.
Laboratory evaluation may include ANA, anti-ro/la, plasma porphyrins, and HLA-DRB1*0407.
Phototesting typically demonstrates normal MEDs to UVB, UVA, and visible light. Photoprovocation testing to UVB and/or UVA is typically positive.

Figure 4.1. CLINICOPATHOLOGICAL CORRELATION: POLYMORPHOUS LIGHT ERUPTION. Characteristic features are papillary dermal edema ± epidermal spongiosis and a predominantly lymphocytic superficial and deep perivascular and periadnexal dermal infiltrate. A. Early PMLE. B. Late PMLE with marked papillary dermal edema. PMLE, polymorphous light eruption.

(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)

Management

Photoprotection is first line. In patients with severe PMLE, prophylactic nbUVB phototherapy in the spring may induce immunologic tolerance.
Topical and/or systemic corticosteroids may be helpful for acute flares. Consider hydroxychloroquine.
- Actinic prurigo often resolves by adolescence, but may persist. Consider thalidomide.

“Real World” Advice

Clinical clues to differentiate PMLE from LE include pruritus and shorter duration (days to weeks as compared to weeks to months).
PMLE is commonly mistaken for a “sunscreen allergy.”
When discussing photoprotection, remind patients that light may trigger PMLE through window glass.

HYDROA VACCINIFORME

Reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.
HV is a rare idiopathic photodermatosis. It typically occurs in light skin toned children with an increased incidence and severity in boys. HV is most severe during the spring and summer. UVA light is the primary trigger. Associations include EBV infection.
HV classically presents with photodistributed macules within hours after light exposure. Lesions evolve into papules and plaques that develop umbilicated vesicles, condense into hemorrhagic crusts, and ultimately heal with varioliform scarring.
- HV progresses from epidermal spongiosis to vesiculation to necrosis to scarring. A predominantly lymphocytic perivascular dermal infiltrate demonstrates positive fluorescence in situ hybridization (FISH) for EBV RNA.
Phototesting typically demonstrates lowered MEDs to UVB and UVA light. Photoprovocation testing to UVA light is typically positive. HV-like CTCL, a type of extranodal NK/T– cell lymphoma, nasal type, is an important consideration.
Photoprotection is first line. While HV is refractory to treatment, it often resolves during adolescence or early adulthood.

CHRONIC ACTINIC DERMATITIS
CAD is a rare idiopathic photodermatosis. The hypothesized pathogenesis is a delayed-type, cell-mediated (type IV) reaction to endogenous cutaneous photoinduced antigens. CAD is most common in men over 50 years of age. UVB and UVA > visible light are triggers.
CAD classically presents with a photodistributed chronic eczematous eruption. Generalization of CAD may lead to erythroderma. Lymphadenopathy is variably present. Actinic reticuloid is a severe CAD variant with pseudolymphomatous papules and plaques.
- CAD can NOT be distinguished from MF on histopathology. However, psoriasiform acanthosis may be a helpful clue. There is a predominance of CD8⁺ T-cells in CAD versus CD4⁺ T-cells in MF. TCR gene rearrangement is often negative.
Phototesting typically demonstrates lowered MEDs to UVB and UVA > visible light. CAD may coexist with airborne ACD (eg, sesquiterpene lactones) and photoallergic eruption/photoallergic contact dermatitis (eg, benzophenones, musk ambrette), yielding positive photopatch testing. Photoaggravated dermatoses (eg, AD) and CTCL are diagnostic considerations.

CAD self-resolves in 10% of patients over 5 years and 20% of patients over 10 years. Photoprotection is first line. Topical and/or systemic corticosteroids and other immunosuppressive agents may be required.

SOLAR URTICARIA

Reprinted with permission from Goodheart HP, Gonzalez ME. Goodheart’s Same-Site Differential Diagnosis: Dermatology for the Primary Health Care Provider. 2nd ed. Wolters Kluwer; 2022.

Solar urticaria is a rare idiopathic photodermatosis. The hypothesized pathogenesis is an IgE-dependent (type I) reaction to endogenous cutaneous photoinduced antigens. Solar urticaria is most common in women in the third decade. Visible > UVA > UVB light are triggers. Associations include SLE and EPP.
Solar urticaria classically presents with photodistributed urticaria ± anaphylaxis within minutes after light exposure that resolves within hours.
- Solar urticaria can NOT be distinguished from other urticarias on histopathology.
Laboratory evaluation may include ANA, anti-ro/la, and plasma porphyrins. Phototesting typically demonstrates wheals within minutes to visible > UVA > UVB light.
Solar urticaria self-resolves in 15% of patients over 5 years and 25% of patients over 10 years. While photoprotection is important, sunscreens often do not provide sufficient protection against visible and UVA light. Oral nonsedating antihistamines are first line.

SPOTLIGHT ON XERODERMA PIGMENTOSUM

Reprinted with permission from Krakowski AC. Procedural Pediatric Dermatology. Wolters Kluwer; 2020.
XP is classified under defective DNA repair and chromosomal instability disorders. It is due to hereditary defects in the nucleotide excision repair (NER) pathway, which repairs UVR damage to cellular DNA (eg, posaconazolepyrimidine dimers).
XP and related disorders are summarized in Table 4.1.
- XP demonstrates UVR-associated histopathological changes (eg, solar lentigines).
Photoprotection is first line.

Table 4.1. XERODERMA PIGMENTOSUM AND RELATED DISORDERS

Diagnosis^a	Inheritance Pattern	Gene(s)	Classic Description	Notes
XP	AR	XPA-XPG	Photosensitivity/poikiloderma. Systemic features include neurologic degeneration (especially DeSanctis-Cacchione syndrome with dwarfism and hypogonadism) and ocular involvement (eg, conjunctivitis).	Impaired NER. Increased risk of BCC, SCC, and melanoma.
XP variant	AR	pol-η	Similar to XP without neurologic degeneration.	Impaired translational DNA synthesis. Increased risk of BCC, SCC, and melanoma.
Trichothiodystrophy with ichthyosis (IBIDS/PIBIDS, Tay syndrome)	AR	ERCC2 encoding XPD > ERCC3 encoding XPB^a (DNA helicases)	Photosensitivity/poikiloderma (˜50%). Ichthyosis (CIE-like) and brittle hair/nails. Characteristic hair shaft abnormalities with increased fragility are trichoschisis and trichothiodystrophy. Systemic features include short stature, intellectual disability, and hypogonadism.	Impaired transcription-coupled NER. Sulfur-deficient hair specifically due to deficiency of the sulfur-containing amino acids cysteine and methionine. Hypogammaglobulinemia. No increased risk of skin cancer.
	AR		IBIDS is described by the name: ichthyosis, brittle hair, intellectual disability, decreased fertility, and short stature. PIBIDS adds photosensitivity.
Cockayne syndrome	AR	ERCC8 encoding CS-A, ERCC6 encoding CS-B (proteins in the TCR complex that respond to DNA damage-stalled RNA polymerase II)	Periorbital atrophy, prominent ears, and photosensitivity/poikiloderma. Systemic features include cachectic dwarfism, neurologic degeneration, pigmentary retinal degeneration, and deafness.	Impaired transcription-coupled NER. Basal ganglia calcification. No increased risk of skin cancer.
Progeria (Hutchinson-Gilford syndrome)	AD	LMNA encoding lamin A and lamin C (nuclear envelope proteins)	Premature aging (disproportionately large cranium with prominent scalp veins, beaked nose, micrognathia, sclerodermoid skin; alopecia). Systemic features include generalized atherosclerosis, poor growth, and highpitched and piping voice.	Onset in the first year of life (median lifespan 14 years). Increased urine HA.
Progeria (Hutchinson-Gilford syndrome)	AD			Patients with progeria are “wasting” a soft-tissue dermal filler used to make people look young.
Adult progeria (Werner syndrome)	AR	RECQL2 (WRN) encoding RECQ2 (DNA helicase)	Premature aging.	Onset in the second decade of life. Increased risk of malignancy (eg, melanoma, meningioma, sarcoma, thyroid cancer).
Do NOT confuse adult progeria (Werner syndrome) with MEN1 (Wermer syndrome)	AR	RECQL2 (WRN) encoding RECQ2 (DNA helicase)	Premature aging.
Bloom syndrome (congenital telangiectatic erythema)	AR	RECQL3 (BLM) encoding RECQL3 (DNA helicase)	CALMs, malar erythema/telangiectasias, and photosensitivity/poikiloderma. Systemic features include short stature, prominent nose, and hypogonadism.	Increased sister chromatid exchanges. Immunodeficiency leading to recurrent otic and pulmonary infections (decreased IgA and IgM ± IgG). Increased risk of SCC, leukemia, lymphoma, and gastrointestinal cancer.
Rothmund-Thomson syndrome (poikiloderma congenitale)	AR	RECQL4 encoding RECQL4 (DNA helicase)	EPS, photosensitivity/poikiloderma; scalp/eyebrow/eyelash alopecia. Systemic features include short stature, radial ray defects (eg, thumb aplasia), and hypogonadism.	Increased risk of SCC and osteosarcoma.
FA	AR > XLR	Variable	CALMs, diffuse hyperpigmentation. Systemic features include pancytopenia, short stature, radial ray defects (eg, thumb aplasia), and hypogonadism.	Enhanced chromosomal breakage and rearrangement. Increased risk of SCC and AML.
DKC (Zinsser-Engman-Cole syndrome)	XLR > AD, AR	DKC1 encoding dyskerin^a	Reticulated hyperpigmentation; premalignant leukoplakia; nail hypoplasia. Systemic features include liver cirrhosis, pancytopenia, epiphora (continuous lacrimation), and pulmonary fibrosis ± posterior fossa malformations (Hoyeraal-Hreidarsson syndrome).	Impaired ribosome activity and telomere maintenance. Bone marrow failure is the leading cause of death. Increased risk of SCC and AML.
A-T (Louis-Bar syndrome)	AR	ATM encoding ATM (kinase)	Cerebellar ataxia presents in infancy. Telangiectasias present between 3 and 6 years of age on the bulbar conjunctivae and spread to head/neck and acral sites. Other cutaneous features include CALMs, non-infectious granulomas, photosensitivity/poikiloderma, and premature aging; premature canities.	Impaired DNA repair, particularly double strand breaks. Sensitivity to ionizing radiation. Defects in humoral and cell-mediated immunity (increased IgM, decreased IgA, IgG, IgE) leading to recurrent sinopulmonary infections. Bronchiectasis with respiratory failure is the leading cause of death. Decreased Purkinje cells in the cerebellum. Increased risk of leukemia and lymphoma. Carriers have an increased risk of breast cancer.
A-T (Louis-Bar syndrome)	AR	ATM encoding ATM (kinase)	Remember that ataxia precedes telangiectasia by the name: ataxiatelangiectasia.
AD, autosomal dominant; AML, acute myelogenous leukemia; AR, autosomal recessive; A-T, ataxia telangiectasia; ATM, ataxia-telangiectasia mutated; BCC, basal cell carcinoma; CALMs, café-au-lait macules; CIE, congenital ichthyosiform erythroderma; CS-A, Cockayne syndrome A; CS-B, Cockayne syndrome B; DKC, dyskeratosis congenita; DNA, deoxyribonucleic acid; EPS, elastosis perforans serpiginosa; FA, Fanconi anemia; HA, hyaluronic acid; IBIDS, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature; Ig, immunoglobulin; MEN, multiple endocrine neoplasia; NER, nucleotide excision repair; OCA, oculocutaneous albinism; PIBIDS, photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature; RNA, ribonucleic acid; SCC, squamous cell carcinoma; XLR, X-linked recessive; XP, xeroderma pigmentosum.
^aIllustrative examples provided. Hereditary disorders with photosensitivity/poikiloderma discussed elsewhere include OCA, Hailey-Hailey disease/Darier disease, Kindler syndrome, cutaneous porphyrias, and Hartnup disease.