American Journal of Medical Genetics 76:217–221 (1998)
Blau Syndrome of Granulomatous Arthritis, Iritis,
and Skin Rash: A New Family and Review of
the Literature
S. Manouvrier-Hanu,1* B. Puech,2 F. Piette,3 O. Boute-Benejean,1 A. Desbonnet,4 B. Duquesnoy,4
and J.P. Farriaux1
1
Consultation de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France
2
Explorations Fonctionnelles de la Vision, Hôpital Salengro, CHRU, Lille, France
3
Service de Dermatologie, Hôpital Huriez, CHRU, Lille, France
4
Service de Rhumatologie, Hôpital Salengro, CHRU, Lille, France
Blau syndrome (MK186580) comprises
granulomatous arthritis, iritis, and skin
rash, and is an autosomal-dominant trait
with variable expressivity. So far it was de-
scribed in 5 families. We report on a sixth
family with severe progression of eye in-
volvement and discuss the nosology with
similar diseases, such as early-infantile sar-
coidosis. Am. J. Med. Genet. 76:217–221,
1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: Blau syndrome; familial;
granulomatous; arthritis;
childhood sarcoidosis;
uveitis
INTRODUCTION
Blau [1985] described a large family whose members
were affected by a disease resembling infantile sarcoid-
osis. This condition (MK186580) is an autosomal-
dominant trait with variable expressivity and com-
prises granulomatous arthritis, iritis, and skin rash.
Five families were described so far. We report on a
sixth family with particularly severe progression of eye
involvement in early adulthood, and review the litera-
ture.
CLINICAL REPORTS
The propositus (Fig. 1, patient 1) is a 32-year-old
Caucasian man referred for genetic counseling because
of his blindness. When he was 4 years old, he had pain-
less synovitis of both wrists and ankles and of the right
knee. The diagnosis of juvenile chronic arthritis was
*Correspondence to: Sylvie Manouvrier-Hanu, Consultation de
Génétique Médicale, Hôpital Jeanne de Flandre, CHRU, 59037
Lille, France.
Received 26 October 1996; Accepted 19 May 1997
© 1998 Wiley-Liss, Inc.
proposed. No further information is available about
that period.
At age 17 years, he was referred for acute nongranu-
lomatous iridocyclitis. He presented with bilateral an-
terior uveitis and disc edema. The disease was slightly
responsive to topical corticosteroids and mydriatics.
Nevertheless, he developed peripheral synechiae and
glaucoma leading to blindness at age 27 years despite
bilateral iridectomy. There was no history of skin erup-
tion, or of pulmonary or inflammatory bowel disease.
At the time of genetic counseling physical examina-
tion showed synovial cysts of wrists and ankles, promi-
nent interphalangeal joints, ‘‘boutonniere’’ (buttonhole)
deformities of the fingers (Fig. 2), and deformities of
the toes. There was no anomaly of the spine. Ophthal-
mologic examination demonstrated complete blind-
ness, large precipitates on the endothelial surface of
both corneae, numerous posterior synechiae, glaucoma
with elevated intraocular tension, and postiritic de-
struction (Fig. 3). No other anomalies were found. Limb
X-rays demonstrated flexion deformities, mild carpal
osteoporosis, periarticular swelling of ankles, wrists,
and knees, narrowing of the first interphalangeal
joints’ spaces, and enlargement of the lower femoral
metaphyses.
Patient 2 is the monozygotic twin of the propositus.
His history is quite similar but with no skin involve-
ment. His synovitis of the wrist and ankles began at
age 4 years, with bilateral uveitis in adolescence lead-
ing to blindness by 29 years despite treatment with
corticosteroids and mydriatics. At 9 years, he under-
went synovectomy of one ankle. Histopathologic exami-
nation showed granulomatous inflammation with giant
cells of Langhans’ type. Results of special stains were
negative for bacteria, acid-fat bacilli, and fungi. Nev-
ertheless, the diagnosis of either tuberculosis or sar-
coidosis was proposed. Physical and X-ray findings at
33 years showed a clinical picture similar to that ob-
served in the propositus.
Patient 3 is one of the sons of the propositus. He was
born after an unremarkable pregnancy. He was
healthy until age 2 years, when he developed a gener-
218 Manouvrier-Hanu et al.
Fig. 1. Pedigree of Blau syndrome family described in this report.
alized (only sparing the palms and soles) skin rash de-
scribed as tiny red dots. A skin biopsy demonstrated
dermal granulomatous infiltration with many epitheli-
oid cells, multinucleated giant cells, and lymphocytes.
According to the mother the skin eruption resolved
spontaneously a few months later. At 8 years he was
referred for a slightly progressive, painless ‘‘bouton-
niere’’ deformation of all digits (Fig. 4), associated with
cysts of the dorsal face of the feet and wrists, and
edema of the wrists and ankles and right knee. Physi-
cal findings were essentially normal in this well-
developed, intelligent boy with exception of the joint
anomalies and a tiny, erythematous and papular skin
eruption on chest, back, and limbs. Eye findings were
normal. Laboratory data were unremarkable; in par-
ticular, there was no evidence of hypergammaglobu-
linemia, rheumatoid factor, DNA antibody, or anti-
nuclear antibody (ANA) production. No HLA B27 was
found. A skeletal survey of the wrists, ankles, hands,
and feet was normal. The boy is now 10 years old, and
no other anomaly has been observed, and particularly
no eye involvement.
Patient 4 is the third child of patient 2. She was born
Fig. 2. Synovial cysts of wrists, prominent interphalangeal joints, and
‘‘boutonniere’’ deformities of the fingers.
at term with intrauterine growth retardation (weight,
2,510 g) due to maternal hypertension. She presented
with left renal dysplasia and underwent unilateral ne-
phrectomy at 12 months. At 7 years she was referred,
with her two sibs, for genetic counseling because of the
diagnosis of Blau syndrome in patients 1–3. On clinical
examination she was a well-developed, intelligent girl.
There was a slight granulomatous eruption on the back
and the chest and a ‘‘boutonniere’’ deformity of the
fourth fingers. No other joint anomaly was observed
and the eyes were normal. X-rays and laboratory data
were unremarkable. A skin biopsy showed noncaseat-
ing granulomas composed of multiple epithelioid cells,
giant cells, and lymphocytes. Electron microscopy did
not show any ‘‘comma-shaped bodies’’ as described in
one previous report [De Chadaverian et al., 1993].
Regarding other relatives, patients 1 and 2 were the
last-born children of healthy, unrelated parents. At the
time of their birth their mother and father were 30 and
29 years old, respectively. None of the 5 sibs of patients
1 and 2 wanted to be examined. Nevertheless, accord-
ing to the propositus, none of them and none of their
offspring have arthritis, chronic uveitis, or rash.
The young brother of patient 3, who is 9 years old,
and the sibs of patient 4, age 11 and 10 years, respec-
tively, were examined. To date none of them present
any skin, joint, or eye anomaly.
DISCUSSION
These 4 patients exhibit at least one, or more, of the
three characteristic organ involvements observed in
Blau syndrome, which is a rare (or rarely diagnosed)
autosomal-dominant disease. To our knowledge, ‘‘typi-
cal’’ Blau syndrome was reported so far in 5 pedigrees
(plus the one described here) [Blau, 1985; Raphael et
al., 1993; Tromp et al., 1996; Pastores et al., 1990; De
Chadaverian et al., 1993; Mau et al., 1995; Moraillon et
al., 1996].
The data presented here and the review should help
to better delineate this disease and its natural history
and to discuss its relationship with childhood sarcoid-
osis. Blau syndrome is described as the unique combi-
nation of tissue-specific inflammation in three organs.
Its clinical phenotype includes granulomatous acute
anterior uveitis, arthritis, and skin rash (Table I).
The leading manifestation is probably a skin rash
(Table I), which was observed as early as age 4 months
[Blau, 1985; Raphael et al., 1993, patient C 18], and
often in early childhood. This rash of tiny red dots is
painless and sometimes so mild, as in patient 4 of this
report, that it could be missed if not carefully searched
for. Moreover, it usually resolves spontaneously, as in
patient 3 of this study. However, we think that skin
involvement was probably underdiagnosed in previous
reports. The histopathological examination of a skin
biopsy shows noncaseating granulomas in the dermis
with multiple epithelioid and multinucleated giant
cells [Blau, 1985; Raphael et al., 1993; Pastores et al.,
1990; De Chadaverian et al., 1993; Moraillon et al.,
1996; this study], similar to those seen in sarcoidosis.
However, electron microscopy in one case showed [De
Chadaverian et al., 1993] ‘‘comma-shaped bodies’’ in

Fig. 3.
the epithelioid cells. This finding has not been reported
in sarcoidosis and could represent a marker for differ-
entiating the granulomas seen in Blau syndrome from
those typical of sarcoidosis. However, the electron mi-
croscopy of a skin biopsy of patient 4 did not demon-
strate any ‘‘comma-shaped bodies.’’
The joint anomalies always appear before age 10
years (Table I). The condition begins insidiously with
painless cysts on the back of feet and wrists, and mild
‘‘boutonniere-deformities’’ of the fingers, which are con-
sidered characteristic findings [Raphael et al., 1993].
They develop progressively to camptodactyly and cystic
swelling of the wrists, ankles, knees, and sometimes
Fig. 4. ‘‘Boutonniere’’ deformation of digits.
Blau Syndrome 219
Postiritic destruction.
elbows. The condition remains mostly painless and
does not lead to severe handicap until the fourth or
fifth decade (decreased large joint motion). Neverthe-
less, camptodactyly may interfere with fine finger
movements as early as childhood. X-ray films mostly
show the flexion deformities associated with periar-
ticular swelling. Narrowing of some joint spaces and
enlargement of some metaphyses, as described in pa-
tients 1 and 2 of this report, are rare [Raphael et al.,
1993, patient III 18]. If a synnovial biopsy is performed
[Blau, 1985; Pastores et al., 1990; De Chadaverian et
al., 1993; this study], granulomatous inflammation is
observed, with giant multinucleated cells.
Eye involvement represents the most severe aspect
of the syndrome. It can appear very early in childhood
[Blau, 1985, index case], or in adulthood [Blau, 1985,
patient III-22]. Usually the initial findings are conjunc-
tival erythema associated with blurring of vision lead-
ing to the diagnosis of uveitis. The proposed treatment
is topical steroids, which sometimes seems to stabilize
the evolution of this inflammatory eye process. How-
ever, the episodes of uveitis tend to become more fre-
quent, progress to posterior involvement, and are as-
sociated with disc edema and perimacular wrinkling.
Later, uveitis becomes complicated by glaucoma, re-
sponsible for blindness many years after the initial eye
manifestations.
Lack of visceral involvement, vasculitis, or fever, as-
sociated with the mode of inheritance, has been consid-
ered sufficient to distinguish Blau syndrome from
childhood sarcoidosis, which is mostly sporadic. Al-
though rare cases of familial early infantile sarcoidosis
220 Manouvrier-Hanu et al.

TABLE I. Clinical Findings in Blau Syndrome Patients and Literature Review*

References Sex Age at onset Skin Joints Eye
Blau, 1985; Raphael et al. [1993];
Tromp et al. [1996]
Propositus (IV-21) F 6m +a + (6 y.) + (7 y.)
I-1 M 1–20 y. +
II-4 F 11–15 y. +
II-5 M 11–15 y. +
II-7 M 16–20 y. +
II-8 M 16–20 y. +
II-10 M 11–15 y. +
III-9 F 16–20 y. +
III-18 F 4 m. +a + (5 y.) + (8 y.)
III-20 M 11–15 y. + (40 y.) +a −
III-22 M 27 y. + (36 y.) − +a
III-25 F 11–15 y. − + −
III-27 M ? ? ? +
III-30 F 5 m. +a + (2 y.) + (12 y.)
IV-24 M 5 y. +a − −
IV-26 F 8 y. − − +a
IV-28 M 2 y. +a + (3 y.) +a
IV-29 M 0–10 y. +a − −
IV-30 F 0–10 y. +a − −
Pastores et al. [1990]
Index case F 2 1/2 y. +a + (3 y.) + (4 y.)
Sister F 10 m. +a + (2 1/2 y.) −
Mother F 8 y. − +a + (13 y.)
De Chadaverian et al. [1993]
Propositus M 8 m. +a + +
Mother F ? + + +
Moraillon et al. [1996]
Propositus M 2 y. + +a −
Father M 6 y. − +a −
Mau et al. [1995] 7–57 y.
10 family members ? Anticipation 7/10 9/10 7/10
This study
Propositus M 4 y. − +a + (17 y.)
Case 2 M 4 y. − +a + (16 y.)
Case 3 M 2 y. +a + (8 y.) −
Case 4 F 6 1/2 y. +a +a −

*y., years; m., months.

a
Leading symptom.

have been described [Rotenstein et al., 1982; Miller,
1986; Hafnerr and Vogel, 1993], these are quite differ-
ent from classical childhood sarcoidosis because of the
very early onset (before age 4 years), frequent arteritis
leading to hypertension, fever, and severe evolution.
Miller [1986] proposed the term ‘‘juvenile systemic
granulomatosis’’ to distinguish this disease from child-
hood sarcoidosis. Moreover, a recent report [Saini and
Rose, 1996] describes ‘‘Blau syndrome’’ with fever and
asymptomatic hepatic granulomas in a child whose
half-brother exhibited polyarthritis due to severe pro-
liferative nongranulomatous synovitis and skin rash.
Their mother had polyarticular arthritis, anterior non-
granulomatous uveitis, and skin lesions suggestive of
erythema nodosum. Jabs et al. [1985] described in an
additional family a disease ressembling Blau syndrome
(association of dominantly-inherited granulomatous
synovitis and bilateral recurrent uveitis) associated
with cranial neuropathies (corticosteroid-responsive
hearing loss and sixth nerve palsy) without skin in-

TABLE II. Differences Between ‘‘Typical’’ and ‘‘Atypical’’ Blau Syndrome and ‘‘Juvenile Systemic Granulomatosis’’

Blau syndrome ‘‘Atypical Blau syndrome’’ Familial juvenile

systemic granulomatosis,
Blau Pastores et De Chadaverian Mau et Moraillon This Jabs et al. Saini and Rotenstein et al. [1982],
[1985] al. [1990] et al. [1993] al. [1995] et al. [1996] report [1985] Rose [1996] Hafnerr and Vogel [1993]
Skin + + + + + + − + +
Joints + + + + + + + + +
Eye + + + − + + + + +
Other findings − − − − − − Cranial Fever, sarcoid- Fever, arteritis,
neuro- like hepatic malignant
pathies granulomata hypertension

volvement, which could have gone undetected. Al-
though these conditions seems to be substantially dif-
ferent from Blau syndrome, many findings are similar
(Table II), so that the nosological question regarding
infantile sarcoidosis and Blau syndrome is a legitimate
one.
Linkage analysis was performed in the family de-
scribed by Blau [1985], and 55 family members were
genotyped for highly polymorphic markers [Tromp et
al., 1994]. These data made it possible to situate the
Blau susceptibility locus on the pericentromeric region
of chromosome 16 (16p12–16q21). It would be of great
interest to test this locus in ‘‘atypical’’ Blau syndrome
and in ‘‘juvenile systemic granulomatosis’’ families.
REFERENCES
Blau EB (1985): Familial granulomatous arteritis, iritis and rash. J Pedi-
atr 107:689–693.
De Chadaverian JP, Raphael SA, Murphy GF (1993): Histologic, ultra-
structural, and immunocytochemical features of the granulomas seen
in a child with the syndrome of familial granulomatous synovitis, uve-
itis and rash. Arch Pathol Lab Med 117:1050–1052.
Häfnerr R, Vogel P (1993): Sarcoidosis of early onset. A challenge for the
pediatric rheumatologist. Clin Exp Rheumatol 11:685–691.
Jabs DA, Houk JL, Bias WB, Arnett FC (1985): Familial granulomatous
synovitis, uveitis and cranial neuropathies. Am J Med 78:801–804.
Mau U, Baykal HE, Erb C, Thiel J, Muller C, Kaiser P, Zierhut M (1995):
Blau Syndrome 221
Blau syndrome (familial non HLA-B27-associated acute anterior uve-
itis with arthritis and skin manifestations): A rare syndrome in a fam-
ily with 10 members over 4 generations. Med Genet 7:180.
Miller JJ (1986): Early-onset ‘‘sarcoidosis’’ and ‘‘familial granulomatous
arthritis (arteritis)’’: The same disease.
Moraillon J, Hayem F, Bourrillon A, Morel P, Rybojab M (1996): Syndrome
de Blau ou forme infantile de sarcoidose à début infantile. Ann Der-
matol Venereol 123:29–30.
Pastores GM, Michels VV, Stickler GB, Su D, Nelson AM, Bovenmyer DA
(1990): Autosomal dominant granulomatous arthritis, uveitis, skin
rash and synovial cysts. J Pediatr 117:403–408.
Raphael SA, Blau EB, Zhang WH, Hsu SH (1993): Analysis of a large
kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis.
Am J Dis Child 147:842–848.
Rotenstein D, Gibbas DL, Majmudar B, Chastain EA (1982): Familial
granulomatous arteritis with polyarthritis of juvenile onset. N Engl J
Med 306:86–90.
Saini SK, Rose CD (1996): Liver involvement in familial granulomatous
arthritis (Blau syndrome). J Rheumatol 23:396–399.
Tromp G, Kuivaniemi H, Raphael S, Ala-Kokko L, Christiano A, Considine
E, Dhulipala R, Hyland J, Jokinen A, Kivirikko S, Korn R, Madhatheri
S, McCarron S, Pulkkinen L, Punnett H, Shimoya K, Spotila L, Tate A,
Williams CJ (1994): Molecular characterization of Blau syndrome: Ge-
netic linkage to chromosome 16. Am J Hum Genet [Suppl] 55:205.
Tromp G, Kuivaniemi H, Raphael S, Ala-Kokko L, Christiano A, Considine
E, Dhulipala R, Hyland J, Jokinen A, Kivirikko S, Korn R, Madhatheri
S, McCarron S, Pulkkinen L, Punnett H, Shimoya K, Spotila L, Tate A,
Williams CJ (1996): Genetic linkage of familial granulomatous inflam-
matory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum
Genet 59:1097–1107.