Genetics in Rheumatology

Classification

Clinical features

Gene/chromosome/OMIM

Protein

Inheritance

Monogenic periodic fevers

Familial Mediterranean fever (FMF)

Recurrent febrile episodes with serositis and arthritis. Long-term development of AA amyloidosis in untreated patients. Good clinical response to colchicine

MEFV (chromosome 16p13.13). OMIM #249100. More than 70 mutations have been reported

Pyrin (marenostrin)

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Recurrent inflammatory attacks lasting 1–3 weeks, with fever, skin rash, arthritis/arthralgia, fatigue, GI involvement. Secondary AA amyloidosis is common in untreated patients

TNFRSF1A (chromosome 12p13.31). OMIM #142680. More than 60 mutations have been reported

TNF receptor 1

AD with incomplete penetrance

Mevalonate kinase deficiency (MKD) or hyper-IgD syndrome (HIDS)

Recurrent inflammatory attacks lasting 3–7 days, with fever, skin rash, arthritis/arthralgia, fatigue, GI involvement

MVK (chromosome 12q24.11). OMIM #260920; #610377. At least 80 mutations have been described

Mevalonate kinase

Cryopyrin-associated periodic syndromes

Familial cold autoinflammatory syndrome (FCAS) 1

Muckle-Wells syndrome (MWS)

Chronic infantile neurological cutaneous and articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID)

Episodes of fever, urticaria-like rash, conjunctivitis, and arthritis. The perinatal-onset form (NOMID) is the most severe presentation, with uveitis, optic nerve atrophy, chronic aseptic meningitis, sensorineural hearing loss. FCAS is the mildest form, while MWS is intermediate in severity

NLRP3/CIAS1 (chromosome 1q44). OMIM #120100; #191900; #607115. Almost all mutations have been described in exon 3

Cryopyrin

NLRP-12-associated autoinflammatory disorder (NLRP12AD) or famlial cold autoinflammtorysyndrome 2 (FCAS2)

NLRP12 (chromosome 19q13.42). OMIM # 611762

Monarch-1

AD with incomplete penetrance

Autoinflammatory granulomatous disorders

Blau syndrome (BS) and early-onset sarcoidosis (EOS) or sporadic form of BS

Clinical presentation is characterized by a triad of arthritis (usually polyarticular), dermatitis, and uveitis. Histologic feature is noncaseating granulomatous inflammation

NOD2/CARD15 (chromosome 16q12.1). OMIM #186580. At least 22 mutations have been found in association with BS

NOD2

AD/sporadic

Autoinflammatory pyogenic disorders

Pyogenic arthritis, pyoderma gangrenosum and cystic acne (PAPA) syndrome

Recurrent and self-limited episodes of pyogenic arthritis, pyoderma gangrenosum, and nodulocystic acne

PSTPIP1/CD2BP1 (chromosome 15q24.3). OMIM #604416

CD2-binding protein

Majeed syndrome (MS) or chronic recurrent multifocal osteomyelitis (CRMO)

Chronic recurrent multifocal aseptic osteomyelitis (CRMO), congenital dyserythropoietic anemia, and neutrophilic dermatoses (such as Sweet syndrome)

LPIN2 (chromosome 18p11.31). OMIM # 609628. At least three mutations have been reported in Middle Eastern families

Lipin 2

AR/sporadic

Deficiency of the interleukin-1 receptor antagonist (DIRA)

Periostitis, pustulosis, nail involvement, CRMO

IL1RN (chromosome 2q14.1). OMIM #612852

IL-1 RA

AD autosomal dominant; AR autosomal recessive; BS Blau syndrome; CARD15 caspase recruitment domain-containing protein 15; CD2BP1 cluster of differentiation 2 binding protein 1; CIAS1 cold-induced autoinflammatory syndrome 1; CINCA chronic infantile neurological cutaneous and articular syndrome; CRMO chronic recurrent multifocal osteomyelitis; DIRA deficiency of the interleukin-1 receptor antagonist; EOS early-onset sarcoidosis; FCAS familial cold autoinflammatory syndrome; FMF familial Mediterranean fever; HIDS hyper-immunoglobulin D syndrome; IL-1 RA interleukin-1 receptor antagonist; MKD mevalonate kinase deficiency; MS Majeed syndrome; MVK mevalonate kinase; MWS Muckle-Wells syndrome; NLRP3 nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3; NLRP12 nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 12; NLRP2AD NLRP12-associated autoinflammatory disorder; NOD2 nucleotide-binding oligomerization domain-containing protein 2; NOMID neonatal-onset multisystem inflammatory disease; OMIM^® Online Mendelian Inheritance in Man^®; PAPA pyogenic arthritis, pyoderma gangrenosum and cystic acne syndrome; PSTPIP1 proline-serine-threonine phosphatase-interacting protein 1; TNF tumor necrosis factor; TNFRSF1A tumor necrosis factor receptor superfamily member 1A; TRAPS tumor necrosis factor receptor-associated periodic syndrome

Familial Mediterranean fever (FMF) is the most common monogenic periodic fever syndrome. FMF is an AR disorder caused by mutations at the MEFV gene which codes for the protein pyrin. Although FMF typically presents during childhood, adult-onset forms can be occasionally seen. The clinical diagnosis is made based on the Tel Hashomer criteria (two major criteria or one major and two minor criteria are needed to make the diagnosis): major criteria, (1) recurrent febrile episodes with serositis (peritonitis, synovitis, or pleuritis), (2) AA amyloidosis without a predisposing disease, and (3) favorable response to regular colchicine treatment; and minor criteria – (1) recurrent febrile episodes, (2) erysipelas-like erythema, and (3) FMF in first-degree relative [1, 8, 20, 21].

TRAPS is a monogenic periodic syndrome with an AD pattern of inheritance, caused by mutations in the TNF receptor superfamily member 1A (TNFRSF1A) gene. TRAPS is characterized by recurrent inflammatory attacks lasting 1–3 weeks, with fever, arthralgia or arthritis, rash, serositis, cramps, myalgia, lymphadenopathy, headache, and fatigue. Secondary AA amyloidosis is common in untreated patients [8, 20, 21].

Mevalonate kinase deficiency (MKD) , formerly known as hyper-immunoglobulin D syndrome, is an AR disorder caused by a mutation in the mevalonate kinase (MVK) gene. Clinically, the inflammatory attacks are characterized by fever, gastrointestinal compromise, skin rash, lymphadenopathy, arthralgia or arthritis, and fatigue. The attacks usually last for 3–7 days and they resolve spontaneously [8, 20, 21].

The cryopyrin-associated periodic syndromes (CAPS) comprise a group of AD disorders that include the familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular (CINCA) syndrome, caused by mutations in the NLRP3/CIAS1 gene that codes for cryopyrin. Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 12 (NLRP12)-associated autoinflammatory disorder (NLRP12AD) is caused by NLRP12 mutation (monarch-1). The CAPS most commonly present in the first 6 months of life, but there have been rare cases reported in adulthood. CAPS commonly present with fever, urticaria-like rash, conjunctivitis, and arthritis, but more specific clinical features depend on the time of onset, with the perinatal form being the most severe presentation (uveitis, optic nerve atrophy, chronic aseptic meningitis, sensorineural hearing loss) [8, 20, 21].

Blau syndrome (BS) and early-onset sarcoidosis (EOS) are autoinflammatory granulomatous disorders caused by mutations in the nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15). BS and EOS present during childhood and have the characteristic histologic findings of noncaseating granulomatous inflammation in affected tissues. BS is transmitted on an AD pattern and presents with a triad of granulomatous arthritis, dermatitis, and uveitis, while EOS is the sporadic form and patients present with polyarthritis with lymphadenopathy and skin and ocular involvement [8, 20, 21].

Pyogenic arthritis, pyoderma gangrenosum and cystic acne (PAPA) syndrome , Majeed syndrome (MS) , and deficiency of the interleukin-1 receptor antagonist (DIRA) are autoinflammatory pyogenic disorders that typically present in early childhood. PAPA syndrome is an AD disorder caused by mutations in the proline-serine-threonine phosphatase-interacting protein 1/cluster of differentiation 2 binding protein 1 (PSTPIP1/CD2BP1) gene. MS is predominantly an AR disorder (although sporadic forms have been described), caused by mutations in the LPIN2 gene coding for lipin-2. DIRA is an AR disorder due to mutations in the IL1RN gene that codes for the interleukin-1 receptor antagonist protein [8, 20, 21].

Genetic Testing in Heritable Disorders of Connective Tissue

The heritable disorders of connective tissue (HDCT) are a heterogeneous group of diseases characterized by defects in several extracellular matrix elements including elastin, collagen, mucopolysaccharides, and many others, producing clinically obvious changes in the skeleton, skin, ligaments, tendons, and other soft tissues [22, 23].

As with the MAIS, genetic testing has allowed a reliable pathway to confirm the diagnosis of many HDCT. Among the clinical features that should lead to a high index of suspicion for HDCT and subsequent genetic testing include joint hypermobility or frequent dislocations, abnormal skin findings (cutis laxa, abnormal scarring, spontaneous bruising, velvety, highly elastic or translucent skin), tissue fragility (multiple hernias or rectal prolapse in early childhood), early-onset hearing loss, ocular findings (ectopia lentis, retinal detachment, scleral fragility, vitreous abnormalities), spontaneous or recurrent pneumo- or hemothoraces, classic cardiovascular abnormalities (early-onset aneurysms, dissections, arterial tortuosity, or family history of any of these disorders), musculoskeletal findings such as pectus excavatum or carinatum, arachnodactyly, brachydactyly, osteoarthritis before age 40, congenital clubfoot or Marfanoid appearance, and craniofacial abnormalities (including cleft palate and hypertelorism), among others [9, 22, 23]. For a summary of clinical findings, affected genes, and the pattern of inheritance of most common HDCT, see Table 19.2.

Table 19.2

Heritable disorders of connective tissue [20–23]

Classification	Clinical features	Gene/chromosome/OMIM	Protein	Inheritance
Ehlers-Danlos syndrome (EDS)
EDS I and II (classic) and EDS V (X-linked)	Joint hypermobility, skin fragility and hyperextensibility, and atrophic scarring. EDS I is the severe classic form and EDS II is the mild type	COL5A1 (chromosome 9q34.3) and COL5A2 (chromosome 2q32.2). OMIM #130000; #130010	Collagen pro-α1 and pro-α2 (V) chains	AD and X-linked
EDS III (hypermobile)	Predominantly joint hypermobility without skeletal deformities, with less severity of skin involvement compared to classic EDS	Unknown. OMIM #130020	Unknown	AD
EDS IV (vascular)	Extensive vascular and intestinal involvement manifested by life-threatening spontaneous rupture of blood vessels and internal organs (intestines or uterus). Translucent skin but only mildly hyperextensible. Mild joint hypermobility (predominantly confined to the fingers)	COL3A1 (chromosome 2q32.2). OMIM #130050	Collagen pro-α1 (III) chain	AD
EDS VI (kyphoscoliotic type 1 and type 2)	Severe muscle hypotonia at birth, generalized joint laxity, scoliosis, Marfanoid habitus, osteopenia, and scleral fragility	PLOD1 (chromosome 1p36.22) and FKBP14 (chromosome 7p14.3). OMIM #225400 and #614557, respectively	Lysyl hydroxylase and FKBP prolyl isomerase 14	AR
EDS VII A and VII B (arthrochalasia type 1 and type 2)	Congenital hip dislocation, extreme joint laxity, recurrent joint subluxations, and minimal skin involvement	COL1A1 (chromosome 17q21.33) and COL1A2 (chromosome 7q21.3). OMIM #130060 and #617821, respectively	Collagen pro-α1 and pro-α2 (I) chains	AD
EDS VIIC (dermatosparaxis)	Dysmorphic features, severe joint hyperextensibility, redundant and fragile skin, short stature, prominent hernias	ADAMTS2 (chromosome 5q35.3). OMIM #225410	Procollagen peptidase	AR
EDS VIII (periodontal type 1 and type 2)	Severe periodontal inflammation, premature teeth loss, skin fragility, easy bruising, generalized joint hypermobility	C1R and C1S (chromosome 12p13.31). OMIM #130080 and #617174, respectively	Complement C1r and C1s	AD
Classic-like EDS	Mild joint hypermobility and skin hyperextensibility (similar to EDS II)	TNXB (chromosome 6p21.33-p21.32). OMIM #606408	Tenascin X	AR
EDS spondylodysplastic type 1 and type 2	Short stature, developmental anomalies of the extremities, joint laxity, skin hyperextensibility, and poor wound healing	B4GALT7 (chromosome 5q35) and B3GALT6 (chromosome 1p36.33). OMIM #130070 and #615349, respectively	β-1,4-Galactosyltransferase 7 and β-1,3-galactosyltransferase 6	AR
EDS musculocontractural type 1 and type 2	Dysmorphic features, congenital contractures of thumbs and fingers, clubfeet, kyphoscoliosis, hypotonia, hyperextensible and fragile skin, joint hypermobility, ocular, cardiac, respiratory, and gastrointestinal involvement	CHST14 (chromosome 15q15.1) and DSE (chromosome 6q22.1). OMIM #601776 and #615539, respectively	Carbohydrate sulfotransferase 14 and dermatan sulfate epimerase	AR
EDS cardiac valvular	Joint hypermobility, skin hyperextensibility, severe cardiac valvular and aortic involvement	COL1A2 (chromosome 7q21.3). OMIM #225320	Collagen pro-α2 (I) chain	AR
EDS myopathic type (Bethlem myopathy 2)	Hypotonia, skin changes, and proximal joint contractures (elbows and ankles)	COL12A1 (chromosome 6q13-q14). OMIM #616471	Collagen type XII α1 chain	AD
Brittle cornea syndrome 1 and 2 (formerly EDS type IVB)	Blue sclerae, corneal abnormalities and rupture after minor trauma, joint hypermobility, and skin hyperextensibility	ZNF469 (chromosome 16q24.2) and PRDM5 (chromosome 4q27). OMIM #229200 and #614170, respectively	Zinc finger protein 469 and PR/SET domain 5	AR
Marfan syndrome and related disorders
Marfan syndrome	Long and thin extremities, tall stature, scoliosis, chest deformities, aortic aneurysms and dilated aortic root, mitral valve prolapse, ectopia lentis, retinal detachments, spontaneous pneumothorax and hernias	FBN1 (chromosome 15q21.1). OMIM #154700	Fibrillin 1	AD with variable expression
Congenital contractural arachnodactyly (arthrogryposis type 9)	Joint contractures, arachnodactyly, scoliosis, osteopenia, abnormally shaped (crumpled) ears	FBN2 (chromosome 5q23.3). OMIM #121050	Fibrillin 2	AD
Loeys-Dietz syndrome 1 and 2	Arterial tortuosity and aneurysms, dysmorphic features (bifid uvula, cleft palate, craniosynostosis, hypertelorism)	TGFBR1 (chromosome 9q22.33) and TGFBR2 (chromosome 3p24.1). OMIM #609192 and #610168	TGF-β receptors 1 and 2	AD
Osteogenesis imperfecta
Osteogenesis imperfecta type I	Bone fragility (fractures with minimal trauma), blue sclerae, hearing loss, thin and fragile skin, joint hypermobility, kyphoscoliosis, mitral valve prolapse, and normal dentition and stature. Most common form	COL1A1 (chromosome 17q21.33). OMIM #166200	Collagen pro-α1 (I) chain	AD/sporadic
Osteogenesis imperfecta type II (perinatal form)	Bone fragility, with many perinatal fractures, severe bowing of long bones, and perinatal death. Most severe form	COL1A2 (chromosome 7q21.3) and COL1A1 (chromosome 17q21.33). OMIM # 166210	Collagen pro-α2 and pro-α1 (I) chains	AD/AR/sporadic/mosaicism
Osteogenesis imperfecta type III (progressively deforming with normal sclerae)	Scleral color (may be blue at birth) normalizes with age, profoundly abnormal dentinogenesis, dysmorphic facial features, progressive deformities of the chest and extremities, severe scoliosis	COL1A2 (chromosome 7q21.3) and COL1A1 (chromosome 17q21.33). OMIM #259420	Collagen pro-α2 and pro-α1 (I) chains	AD/AR/sporadic
Osteogenesis imperfecta type IV (with normal sclerae)	Bone fragility of variable severity, occasional bowing of long bones, abnormal dentinogenesis may be present, scleral color lightens to white with age	COL1A2 (chromosome 7q21.3) and COL1A1 (chromosome 17q21.33). OMIM #166220	Collagen pro-α2 and pro-α1 (I) chains	AD/AR/sporadic
Osteogenesis imperfecta type V (with normal sclerae)	Hyperplastic callus formation, calcification of interosseous membranes, moderate to severe bone fragility of long bones and vertebral bodies, deformities, without abnormal dentinogenesis or blue sclerae	IFITM5 (chromosome 11p15.5). OMIM #610967	Interferon-induced transmembrane protein 5	AD

AD autosomal dominant, ADAMTS2 a disintegrin and metalloproteinase with thrombospondin motifs 2, AR autosomal recessive, B3GALT6 β-1,3-galactosyltransferase 6, B4GALT7 β-1,4-galactosyltransferase 7, CHST14 carbohydrate sulfotransferase 14, COL1A1 collagen type I alpha 1, COL1A2 collagen type I alpha 2, COL12A1 collagen type XII alpha 1, COL3A1 collagen type III alpha 1, COL5A1 collagen type V alpha 1, DSE dermatan sulfate epimerase, EDS Ehlers-Danlos syndrome, FKBP14 FKBP prolyl isomerase 14, IFITM5 interferon-induced transmembrane protein 5, OMIM^® Online Mendelian Inheritance in Man^®, PLOD1 procollagen-lysine,2-oxoglutarate 5-dioxygenase 1, PRDM5 PR/SET domain 5, TGF-β transforming growth factor-β, TGFBR1 TGF-β receptor 1, TGFBR2 TGF-β receptor 1, TNXB tenascin XB, ZNF469 zinc finger protein 469