European Journal of Haematology ISSN 0902-4441

CASE REPORT

Generalized cutis laxa and fibrillar glomerulopathy resulting

from IgG Deposition in IgG-lambda Monoclonal
Gammopathy: pulmonary hemorrhage during stem cell
mobilization and complete hematological response with
bortezomib and dexamethasone therapy
Carlos Fernandez de Larrea1, Montserrat Rovira1, Jose M. Mascaro Jr.2, Albert Torras3, Manel Sole4,
Josep Lloreta5, Nuria Serra3, Maria Teresa Cibeira1, Joan Blade1
1

Departments of Hematology; 2Dermatology; 3Nephrology; and 4Pathology, Hospital Clnic de Barcelona, Institut dInvestigacions Biome`diques
August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 5Department of Pathology, Hospital del Mar. Barcelona, Spain

Abstract
The case of a 52-years-old man with generalized acquired cutis laxa associated with IgG-lambda monoclonal gammopathy and nephrotic syndrome with renal failure (due to fibrillar glomerulopathy resulting
from IgG deposition) is reported. A peripheral blood autologous stem cell transplant was planned, but the
procedure was complicated by severe pulmonary hemorrhage during stem cells mobilization with granulocyte colony-stimulating factor (G-CSF). Treatment with bortezomib and dexamethasome was subsequently
started and a complete hematological response was achieved. Finally, the complete hematological
response with the disappearance of the toxic M-protein allows the possibility of a long-term benefit with a
kidney transplant followed by an autologous bone marrow transplant.
Key words generalized cutis laxa; monoclonal gammopathy; autologous transplant; pulmonary hemorrhage; renal failure; bortezomib
Correspondence Joan Blade, MD, Servei dHematologia, Hospital Clnic de Barcelona. Villarroel 170, 08036 Barcelona, Spain. Tel:
34 93 227 54 28; Fax: 34 93 227 54 84; e-mail: jblade@clinic.ub.es
Accepted for publication 23 October 2008

Background

Cutis laxa (CL) is an exceedingly rare inherited or

acquired skin disorder resulting from alterations in the
elastic bers of the skin (1) The clinical picture consists
of an inelastic skin, that looks loose and pendulous predominately in body fold areas of the axilla, groin or neck
(2). This gives a picture of premature ageing that will
usually be the main patient complain. This syndrome, in
its acquired form, has been associated with many etiologies, such as penicillamine and isoniazid administration
(3, 4), Borrelia infections (5), celiac disease (6) or systemic lupus erythematosus (7). In a few cases, it has been
reported in association with multiple myeloma, as well as
with B and T cell lymphomas (1, 2, 8, 9). Herein, the
case of patient with acquired generalized CL associated
with IgG-lambda monoclonal gammopathy who also
presented a brillar glomerulopathy (resulting from

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doi:10.1111/j.1600-0609.2008.01181.x

IgG-deposition) rapidly evolving to renal failure is

reported. A severe pulmonary hemorrhage developed
during stem cells mobilization with granulocyte colonystimulating factor (G-CSF). The patient subsequently
achieved a hematological complete response with bortezomib and dexamethasone therapy. To our knowledge
this is the rst report of a patient with generalized
acquired CL complicated by G-CSF-induced pulmonary
hemorrhage, and also the rst successfully treated with
bortezomib dexamethasone.
Case report

A 52-years-old white man presented to another institution in August 2006 complaining of progressive changes
in his skin that had appeared over the last 2 yr. This was
associated with an unmeasured weight loss. His past

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Fernandez de Larrea et al.

Cutis laxa, glomerulopathy and monoclonal gammopathy

Figure 1 Inelastic skin, that looks loose and

pendulous in body fold areas of the neck (A)
and axilla (B).

medical history was unremarkable. Clinical exam only

revealed high blood pressure and an inelastic and pendulous skin on his face, neck, axillae and groins. Routine
laboratory work-out demonstrated a creatinine of
1.2 mg dL and a serum M spike of 2.3 g L in the
gamma region. A skin biopsy had been performed and
was considered to be consistent with morphea. The
patient was treated with amlodipine for his high blood
pressure.
He was rst seen at our institution 1 yr later, in June
2007. The mentioned skin changes of generalized CL that
gave a premature ageing appearance (Fig. 1), as well as
discrete bilateral maleolar edemas was seen. A mild
normocytic and normochromic anemia of 110 g L was
noted. However, his creatinine value had risen up to
2.7 mg dL, with a 24-h urine protein excretion of 2.7 g
showing a glomerular pattern. At this time, his serum M
spike was of 4.4 g L. Serum and urine immunoxation
revealed an IgG-lambda monoclonal protein. A bone
marrow aspirate disclosed 5% bone marrow plasma cells
consistent with monoclonal gammopathy of uncertain
signicance. A second skin biopsy (Fig. 2) showed normal appearing dermis and epidermis specic with no
inammatory inltrates on hematoxylin and eosin routine stains. Using orcein stain for elastic bers there was
a marked reduction of the number of elastic bers
throughout the dermis, with absent elastic bers in some
areas (Fig. 2). Direct immunouorescence studies
revealed deposition of IgG along the basement membrane zone of the dermoepidermal junction, the periadnexial and perivascular areas, and in some remaining
elastic bers in the dermis (Fig. 2). A renal biopsy
showed a brillar glomerulonephritis (GN), with negative
Congo red staining (Fig. 3). Electronic microscopy
showed brils ranging from 10 to 15 nm. Although brils
in brillary GN are reported to be thicker (1030 nm),
and amyloid brils are 812 nm thick, the distinction
between these two entities cannot be made on bril
diameter alone. In fact, in one series, average bril diameter in brillary GN was 14 nm (range 10.418.4) (10).
Negative Congo Red and amyloid P-component, as well
as the typical morphologic and immunohistochemistry
ndings were the diagnostic clues in this case.
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Figure 2 Skin biopsies: Hematoxylin and eosin routine stains 100

(A) shows normal appearing dermis and epidermis. Using orcein stain
100 for elastic fibers (B) there was a marked reduction of the number of elastic fibers throughout the dermis, with absent elastic fibers
in some areas. Skin direct immunofluorescence 100 (C) shows IgG
deposition along the basement membrane zone of the dermoepidermal junction, the periadnexial and perivascular areas.

Electrocardiogram,
pulmonary
functional
tests,
abdominal ecography and CT body scan were normal.
Echocardiography only showed a mild mitral regurgitation, with normal interventricular septum and normal
global motility. He was diagnosed with IgG-lambda
monoclonal gammopathy associated with generalized

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Fernandez de Larrea et al.

Cutis laxa, glomerulopathy and monoclonal gammopathy

Figure 3 Kidney biopsy: The optical appearance of glomeruli (A) is consistent with fibrillary glomerulonephritis, showing mesangial expansion,
sometimes nodular, PAS-positive, with some mesangial hypercellularity and a small crescent in one glomerulus. Congo Red and amyloid P-component immunostaining were negative. Immunofluorescence was positive for IgG in the mesangial deposits, whereas light chains were negative.
(PAS 200). Randomly arranged fibrils (B), diameters ranging from 10 to 15 nm (TEM 20 000).

adquired CL and brillar glomerulopathy with nephrotic

syndrome and severe renal failure, both presumably secondary to IgG immunoglobulin deposition. The patient
was otherwise in good general condition and so an autologous peripheral blood stem cell transplant was planned.
On the third day of stem cell mobilization with GCSF, the patient complained of sudden dyspnea with
hemoptysis that rapidly evolved into acute respiratory
failure. Chest x-ray examination and a thorax CT scan
showed extensive bilateral pulmonary inltrates. All
these ndings, associated with a signicant decrease in
the hemoglobin levels and increased LDH levels at 1088
UI L, were consistent with alveolar hemorrhage. The
creatinine reached 10 mg dL and hemodialysis was initiated. The patient improved with non-invasive mechanical
ventilation, as well as treatment with high dose steroids,
broad spectrum antibiotics and packed red cells transfusion support. He was nally discharged from the hospital
and due to the impossibility of stem cell mobilization
and the good clinical status after recovering from his
pulmonary hemorrhage, he was started on a therapeutic
program with i.v. bortezomib 1.3 mg m2 on days 1, 4, 8
and 11, and oral dexamethasone on days 14 and 912
at 3-wk interval. The patient has so far received 6 cycles,
with a complete hematological response (disappearance
of the M-spike on serum and urine electrophoresis and
negative immunoxation with no increase in bone marrow plasma cells). Up to now he is still on a chronic hemodialysis program. His cutaneous condition of CL has
not progressed and surgical correction of redundant skin
folds is planned in the near future.
Discussion

Adquired CL is a rare condition that has been associated

with monoclonal gammopathies very infrequently. Only
seven cases of generalized CL associated with myeloma
and four cases in the context of other plasma cell dyscra-

156

sia have been previously reported (11). Lambda light

chains have been the most frequently involved, although
kappa light chains have also been reported (12). Light
chains, and even heavy IgG monoclonal proteins have
been associated with elastolysis of the skin and glomerular alterations (2, 9).
Involvement of multiple organs by generalized elastolysis, including the gastrointestinal and genitourinary
tracts, lung and cardiovascular systems, have also been
reported (2). Pulmonary involvement, usually with features of emphysema, has been related to elastic bers
breakdown and loss of tissue support (13). Some authors
have suggested that acquired CL could be related to an
underlying genetic susceptibility associated to chronic
inammation (14). Patients with acquired CL can also
develop pulmonary complications such as pneumothorax,
mediastinal emphysema and pneumonia. Pulmonary
involvement may also lead to secondary heart failure. To
our knowledge, the occurrence of pulmonary hemorrhage
in patients with CL has not been previously recognized.
A differential diagnosis in this case should include
gelsolin amyloidosis, a hereditary form of amyloidosis.
The main clinical manifestations are cutis laxa, corneal
lattice dystrophy and cranial polyneuropathy (15). The
clinical cutaneous picture is similar, probably due to
direct toxic effect or an altered elastic brillogenesis (16).
Our patient did not have any neurological alteration
and, mainly, the serum M-spike and skin immunostaing
revealed the presence of an IgG component. Moreover,
the skin biopsy in gelsolin amyloidosis shows congophylic amyloid at the basement membranes and eccrine
sweat, sebaceous glands and hairy follicules with fragmented elastic bers (16). Renal involvement is infrequent, mainly as minor intermittent proteinuria,
although nephrotic syndrome has been also described
(17).
High-dose therapy followed by stem cell rescue has
been shown to be effective in a multiple myeloma (18,

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Fernandez de Larrea et al.

19) and in other plasma cell dyscrasias. Thus, previous

experiences in monoclonal gammopathies with systemic
involvement and post transplant signicant improvement
include POEMS syndrome (20), scleromyxedema, (21,
22) and primary systemic amyloidosis (23). On the basis
of this evidence, high-dose therapy followed by peripheral blood stem cell rescue was planned in our patient
with the hope of improving the skin and kidney involvement by decreasing the toxic IgG M-protein. The development of an acute respiratory failure triggered by stem
cell mobilization with G-CSF was completely unexpected. In vitro studies and occasional previous reports
showed that the use of G-CSF can result in pulmonary
toxicity, ranging from exacerbation of previous lung disease to acute lung injury, including severe pulmonary
hemorrhage. Such events have been reported in patients
with previously unrecognized respiratory tract involvement by amyloidosis, bleomycin lung toxicity and even
in healthy donors (2426). Granulocyte colony-stimulating factor-induced pulmonary toxicity may result from
migration of neutrophils to vascular spaces, adhesion of
neutrophils to previously injured endothelial cells, and or
potentiation of proinammatory cytokines (27). It is
likely that the involvement of perivascular support in the
lung, similar to skin elastolysis, was the main factor contributing to the alveolar hemorrhage in our patient.
Using the same rationale as in other plasma cells dyscrasias, the patient was given treatment with bortezomib
and dexamethasone. This combination has been shown
to be highly effective in patients with multiple myeloma
and with primary systemic amiloydosis (23, 28, 29). In
addition, it can be safely administered at the usual dosing in patients with renal failure. In a series of 24
patients with dialysis dependent myeloma, the overall
response rate was 75% and with no increased toxicity
(30). Interestingly, Ludwig et al. have recently reported
the reversal of acute paraprotein-induced renal failure
with bortezomib-based therapy in ve of eight patients
with multiple myeloma (31). These authors suggested
that bortezomib may accelerate the kidney response, not
only through a rapid decrease in the M-protein concentration, but also through its NF-jB inhibitory effect,
directly reducing the inammation in myeloma kidney
(32). With this background, treatment with bortezomib
and dexamethasone was initiated in our patient. After six
cycles of such therapy a stringent complete hematological
response was achieved. As the M-protein component has
disappeared, a kidney transplant followed of an autologous bone marrow transplantion in order to intensify the
hematological response has been planned.
To conclude, CL syndrome related to monoclonal
gammopathy is a well recognized but extremely infrequent disease. The possible involvement of other organs
such of kidney or lung should be considered before any
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Cutis laxa, glomerulopathy and monoclonal gammopathy

treatment is started. Although there is no previous

experience in the treatment of this condition, the use of
therapeutic strategies against the plasma cell clone
seems most appropriate. However, physicians should be
aware of the possibility of pulmonary complications
with G-CSF mobilization if a peripheral blood autologous stem cell transplant is planned. The dramatic
hematological response with the disappearance of the
M-protein allows the possibility of a kidney transplant
with no risk of immediate damage by the nephrotoxic
IgG M-protein as well a subsequent safer autologous
bone marrow transplant to intensify the hematological
response, this increasing the likelihood of a better longterm outcome.
Acknowledgements

This work has been supported in part by grants 2003RED6-136-0, FIS V-2005-F55240-O, RD 2006 0020 005,
FIS08 0147, CM07 00107 and CM07 00108 from Fondo
de Investigaciones Sanitarias de la Seguridad Social.
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