Genetic Autoinflammatory Disorders

Matthew D. Vesely

Chyi-Chia Richard Lee

Edward W. Cowen

The concept of autoimmunity (horror autotoxicus) was initially proposed over a century ago by Paul Ehrlich to describe the clinical scenario whereby the components of adaptive immunity damage normal tissue.¹ In contrast, autoinflammation (horror autoinflammaticus), a term originally proposed in 1999, describes damage to normal tissue induced by innate immunity.²,³ Although the immune system is divided into innate and adaptive components, they are intricately linked and function in equilibrium. Perturbations in the adaptive immune system often result in an imbalance among innate immune components; thus, neither autoimmunity nor autoinflammatory disorders have defects isolated to a single branch of the immune system. Nevertheless, a preponderance of innate dysregulation is the characteristic feature of autoinflammation.⁴ Defects in the distinct components of innate immunity, in turn, may result in disorders with unique clinicopathologic features. All disorders described herein are rare, monogenic conditions affecting the pediatric population (Table 13-1).

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME (CAPS)

Definition and Epidemiology

Cryopyrin-associated periodic syndrome (CAPS) is a rare disorder of childhood-onset, characterized by systemic and tissue-specific inflammation of the integumentary, nervous, and musculoskeletal systems.⁵ Three related, but distinct, phenotypes encompass the clinical spectrum of CAPS and are referred to as cryopyrinopathies because they have all been linked to mutations in the gene-encoding cryopyrin [CIAS1 (cold-induced autoinflammatory syndrome 1), also known as NLRP3 (NACHT domain, leucine-rich repeat, and pyrin-containing protein 3)]. The mildest phenotype is familial cold autoinflammatory syndrome (FCAS), followed by Muckle-Wells syndrome (MWS), which is associated with more systemic inflammation. The most severe phenotype is neonatal-onset multisystem inflammatory disease (NOMID), which is sometimes referred to in Europe as chronic infantile neurological cutaneous and articular (CINCA) syndrome.

MWS was originally described in 1962 in northern European kindreds who suffered recurrent, severe, acute inflammatory episodes.⁶ Subsequently, MWS, FCAS, and NOMID/CINCA were all found to be caused by mutations in the NRLP3 gene.⁷,⁸,⁹,¹⁰,¹¹ It is estimated that CAPS affects 1:1 000 000 people worldwide.¹² However, the true prevalence may be higher, given unfamiliarity among clinicians and the milder phenotype of FCAS that presents in later childhood.¹³ In France, the incidence of CAPS has been estimated to be as high as 1:360 000 people.¹⁴ The age of presentation varies with severity, with the most severe phenotype, NOMID, developing within days of birth, whereas the symptoms of FCAS may be delayed for several years.

Etiology

The cryopyrinopathies are associated with autosomal dominant or de novo mutations of NLRP3/CIAS1, which encodes the protein cryopyrin. The hallmark of the innate immune dysregulation of CAPS is excessive production of
interleukin-1β (IL-1β). Cryopyrin is a critical component of the inflammasome, a multiprotein complex responsible for generation IL-1β in response to pathogens or “danger signals” from dead or dying host cells. NLRP3 mutations in patients with CAPS appear to activate the inflammasome in the absence of pathogenic insults.³ Nearly all patients with FCAS and MWS have inherited mutations in NLRP3, whereas NLRP3 mutations found in NOMID patients tend to occur de novo.¹⁰ Furthermore, about half of patients with NOMID do not have detectable germline NLRP3 mutations; however, many somatic mutations have been found in these patients.¹⁵

TABLE 13-1. Clinical features, histology, and genetics of selected autoinflammatory syndromes with unique histopathologic features

Disease	Gene	Skin Findings	Systemic Manifestations	Histology
CAPS	NLRP3/CIAS1 Cryopyrin	Urticaria-like eruptions	Fevers arthralgia, eye disease, amyloidosis, neurologic symptoms	Superficial perivascular, and perieccrine infiltrate of mature neutrophils
DIRA	IL1RN IL-1 antagonist	Erythematous plaques with follicular pustules	Periostitis, multifocal osteomyelitis, hepatosplenomegaly	Hyperkeratosis, epidermal, and dermal neutrophilic infiltrate with follicular pustules
DADA2	CERC1 ADA2	Livedo racemosa and painful, pink nodules	Early-onset stroke	Medium-vessel vasculitis
SAVI	TMEM173 STING	Telangiectatic-purpuric plaques on acral sites, progression to ulcers and eschars, nasal cartilage destruction	Fever, failure to thrive, interstitial lung disease	Vasculopathy with neutrophilic infiltrate, karyorrhexis, intravascular thrombosis,s and fibrinoid necrosis of small vessels
CANDLE Syndrome	PSMB8 PSMB8	Annular violaceous plaques, periorbital edema, lipodystrophy	Fevers, organomegaly, arthralgia	Perivascular and interstitial atypical mononuclear infiltrate composed of immature neutrophilis and myeloid precursors
Blau Syndrome	CARD15/NOD2 CARD15/NOD2	Densely populated, small red-brown papules	Fever, granulomatous uveitis, polyarthritis, camptodactyly; granulomatous kidney, liver, lung, and CNS disease	Multicentric, noncaseating, sarcoidtype granulomas, with emperipolesis of lymphocytes in giant cells
Abbreviations: ADA2, adenosine deaminase 2; CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature; CAPS, cryopyrin-associated periodic syndrome; CNS, central nervous system; DADA2, deficiency of adenosine deaminase; DIRA, deficiency of the interleukin-1 receptor antagonist; SAVI, STING-associated vasculopathy with onset in infancy.

Clinical Presentation

CAPS present with urticaria-like papules and plaques, conjunctivitis, fevers, arthralgia, and constitutional symptoms.⁵,¹⁶ In the case of FCAS, symptoms are triggered within hours of exposure to cold temperatures, resulting in an effervescent urticarial rash followed by scleral injection, fever, and arthralgia, which typically last less than 24 hours. Nonpruritic, erythematous papules, and plaques coalesce to form polycyclic or geographic plaques predominantly on trunk and extremities (Figure 13-1A and B). In patients with MWS, a similar presentation with effervescent urticarial rash, fever, conjunctivitis, and arthralgia occurs in the absence of cold exposure. Acute inflammatory episodes typically last 24 to 48 hours, and many patients with MWS experience daily symptoms of chronic systemic inflammation including pain (eg, abdominal) and fatigue. Long-standing systemic inflammation results in secondary amyloidosis, and neurologic involvement results in sensorineural hearing loss. The most severe CAPS phenotype, NOMID, is characterized by daily, persistent attacks of fever, urticarial rash, and arthralgia. A defining feature of NOMID is central nervous system (CNS) inflammation, resulting in chronic aseptic meningitis, seizures, cognitive impairment, and hearing and vision loss.¹⁶,¹⁷,¹⁸ Extensive bone and joint involvement results in deforming arthropathy with epiphyseal bone formation (Figure 13-1C), joint contractures with limited mobility, and abnormal facial features with frontal bossing and flattening of the nasal dorsum.

Histologic Findings

A skin biopsy of the erythematous and edematous papules and plaques in patients with CAPS shows superficial perivascular and perieccrine infiltrate predominately composed of mature neutrophils and dilated superficial dermal lymphatics (Figure 13-2).¹⁹,²⁰ This is in contrast to the typical superficial perivascular lymphocytic inflammatory infiltrate of classic allergic urticaria. In addition, a helpful identifying
feature is characteristic perieccrine neutrophilic infiltration similar to neutrophilic eccrine hidradenitis.²¹ There is an absence of karyorrhexis or leukocytoclasis and vasculitis. There are no epidermal changes and no eosinophils.

FIGURE 13-1. Cryopyrin-associated periodic syndrome. Urticaria-like papules and plaques in a patient with neonatal-onset multisystem inflammatory disease (NOMID) (A) and Muckle-Wells syndrome (B). C, Extensive bone and joint involvement resulting in deforming arthropathy in a patient with NOMID.

FIGURE 13-2. Histology of neonatal-onset multisystem inflammatory disease. A, The epidermal changes are unremarkable. There is mild papillary dermal edema with superficial perivascular and perieccrine infiltrate of mature neutrophils and dilated superficial dermal lymphatics. There is no histologic evidence of vasculitis. B, Characteristic perieccrine neutrophilic infiltration shows an infiltrate of mature neutrophils between eccrine glands.

Differential Diagnosis

Classic urticaria is composed of superficial perivascular infiltrate of lymphocytes and may contain eosinophils. However, a subset of patients with urticaria will present with predominately neutrophil-rich infiltrate, termed neutrophilic urticaria.²² Since the introduction of the term “neutrophilic urticaria,” there have been numerous subtypes described, including autoimmunity-related neutrophilic dermatosis²³, neutrophilic urticaria with systemic inflammation²⁴, and neutrophilic urticarial dermatoses.²⁵ These various subtypes are all characterized by superficial perivascular neutrophilic
inflammation and leukocytoclasis, but there is an absence of perieccrine involvement, vasculitis, or dermal edema. The histologic pattern found in CAPS characteristically involves perieccrine neutrophilic infiltration but lacks significant leukocytoclasis. Urticarial vasculitis has the presence of both leukocytoclasis and vasculitis. Sweet syndrome is characterized by an intense dermal infiltration of neutrophils with leukocytoclasis and significant dermal edema.

CAPSULE SUMMARY

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME

CAPS is a group of rare, inherited autoinflammatory disorders that represent a spectrum of disease severity. NOMID/CINCA is the most severe form. Autosomal dominant or de novo gain-of-function mutations in NLRP3, a component of the inflammasome, result in an overproduction of IL-1β. The clinical features include acute episodes of fever, arthralgia, and urticaria-like eruptions. CNS inflammation is a hallmark of NOMID/CINCA. The histology of CAPS skin lesions is characterized by superficial perivascular and perieccrine infiltrate of mature neutrophils without eosinophils, leukocytoclasis, or vasculitis. Perieccrine neutrophilic infiltration and an absence of leukocytoclasis may help distinguish CAPS from other neutrophilic urticarial dermatoses.

DEFICIENCY OF THE INTERLEUKIN-1 RECEPTOR ANTAGONIST

Definition and Epidemiology

Deficiency of the interleukin-1 receptor antagonist (DIRA) is a rare autoinflammatory disorder characterized by sterile multifocal osteomyelitis and periostitis, with skin lesions resembling pustular psoriasis in the neonatal period.²⁶,²⁷ Autosomal recessive mutations in interleukin-1 receptor antagonist (IL1RN) result in uncontrolled IL-1α/β signaling.²⁶,²⁷

Reports of DIRA to date are predominately described in patients of Puerto Rican, Newfoundland, Lebanese, Dutch, and Brazilian descent.²⁶,²⁷,²⁸,²⁹ The worldwide incidence is unknown given its rarity, but the condition is associated with an estimated 30% mortality during infancy if untreated. It is estimated that 0.2% of the population in Newfoundland are carriers of the mutation with likely similar rates in Lebanon, Brazil, and the Netherlands. The carrier rate in Puerto Rico is approximately 1.3% due to a founder effect, and in the Arecibo region, it is estimated that DIRA may occur in 1:6300 people.²⁶

Etiology

DIRA is caused by autosomal recessive mutations in IL1RN. The lack of a functional IL1RN in DIRA patients results in an unopposed stimulation of the IL-1 receptor by IL-1α and IL-1β.³⁰ IL-1β is processed by the myeloid cells of the innate immune system by the inflammasome, whereas IL-1α is preformed and can be released by nonimmune cells such as keratinocytes and endothelial cells.³⁰ The downstream effects of IL-1α/β result in the production of additional proinflammatory cytokines including tumor necrosis factor (TNF) and IL-17. Although CAPS is the result of the overproduction and secretion of IL-1β, DIRA is the result of an inability to terminate signaling from both IL-1β and IL-1α. In addition, the IL-1 receptor is highly expressed within the epidermis, and unopposed signaling by IL-1α may be responsible for the epidermal changes including hyperkeratosis and subcorneal pustulosis seen in DIRA.

Clinical Presentation

At birth or within a few weeks of age, neonates with DIRA develop a pustular rash, swollen joints, pain with movement, and oral mucosal ulcers.³¹ Of note, fever is characteristically absent despite the elevation of inflammatory markers and acute phase reactants. DIRA in utero resulting in fetal demise has also been reported.³² The rash may consist of discrete erythematous plaques studded with follicular pustules or evolve to generalized pustulosis. Less commonly, ichthyosiform skin changes and nail changes including pitting and onychomadesis are present (Figure 13-3). Superficial trauma of the skin results in pathergy and subsequent pustulosis at the sites of trauma. Although the initial clinical presentation may be confused with pustular psoriasis, the early onset of disease, together with neonatal distress and markers of systemic inflammation, including periostitis, multifocal sterile osteomyelitis, and hepatosplenomegaly, are characteristic of DIRA. The most common radiographic findings include balloon widening of the anterior rib ends, multifocal osteolytic lesions, and periosteal elevation. CNS vasculitis has also been reported.²⁶ Untreated DIRA results in death during infancy or early childhood from multisystem shock and organ failure secondary to overwhelming systemic inflammation. Treatment with IL-1 blockers is lifesaving.²⁶

Histologic Findings

The cutaneous biopsies of the pustular rash show a dense infiltrate of mature neutrophils throughout the dermis with acanthosis, intraepidermal neutrophils, prominent papillary dermal edema, and pustule formation along the hair follicular infundibulum (Figure 13-4).²⁶,²⁷ Notably, there is a combination of subcorneal pustules as well as dense neutrophilic infiltrate with a destruction of hair follicular infundibula. One patient had histopathologic evidence of vasculitis in the subcutis adjacent to bone inflammation.²⁶

Differential Diagnosis

The histopathologic differential diagnosis of DIRA includes other causes of subcorneal pustules. The key distinguishing
feature of DIRA is folliculocentric infiltrate of neutrophils with involvement of the follicular infundibula, as other disorders that present with subcorneal pustules rarely involve the hair follicle. Pustular psoriasis may show features common in more chronic plaque psoriasis such as an elongation of rete ridges, papillary epidermal thinning, and dilated, tortuous papillary vessels. In addition, the lesions of pustular psoriasis are characterized by parakeratosis, spongiosis, and the spongioform pustules of Kogoj. Deficiency of IL-36 receptor antagonist (DITRA) also presents with an erythematous pustular rash mimicking psoriasis but lacks internal organ manifestation.³³,³⁴,³⁵ The histology of DITRA demonstrates spongiform pustules, acanthosis, and parakeratosis.³⁴ Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) shows perivascular neutrophilic infiltrate with occasional monocytes and eosinophils. Acute generalized exanthematous pustulosis is nonfollicular and often contains eosinophils.

FIGURE 13-3. Deficiency of the IL-1 receptor antagonist. A, Erythroderma, pinpoint pustules, and ichthyosiform scale in a neonate. B, Nail changes including pitting and onychomadesis.

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