Elbow Deformities in a Patient With MandibuloacralDysplasia Type AValeria Guglielmi,1 Monica DAdamo,1 Maria Rosaria DApice,2 Alfonso Bellia,1 Davide Lauro,1
Massimo Federici,1 Renato Lauro,1 Giuseppe Novelli,2 and Paolo Sbraccia1*1Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy2Department of Biopathology and Diagnostic Imaging, University of Rome Tor Vergata, Rome, Italy
Received 6 May 2010; Accepted 12 July 2010
TO THE EDITOR:
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive
disorder characterized by postnatal growth retardation, craniofa-
cial anomalies, mandibular hypoplasia with dental overcrowding,
micrognathia and narrow nasal bridge and tip, skeletal anomalies
(progressive osteolysis of the clavicles and distal phalanges, delayed
closure of the cranial sutures, and joints contractures) and skin
changes including mottled hyperpigmentation and atrophy. We
and others have already reported lipodystrophy and metabolic
complications associated with insulin resistance in patients affected
with MAD [Novelli et al., 2002; Simha and Garg, 2002; Simha et al.,
Thus far, several mutations in LMNA gene have been reported in
23 patients (type A MADMADA) while only four patients havebeen reported with ZMPSTE24 mutations (type B MADMADB)[Shackleton et al., 2005; Agarwal et al., 2006]. The allelic hetero-
geneity of MADA patients is accompanied by phenotypic variability
and expressivity, concerning appearance, age of onset, progression
and severity degree of some clinical features.
We describe elbow deformities in a previously characterized
male 43-year-old patient, with homozygous LMNA missense mu-
tation (R527H) [Novelli et al., 2002], who is the second oldest
studied MADA patient [Kosho et al., 2007].
The patient developed, over a period of nearly 2 years, deforma-
tion and swelling of the right elbow, associated with pain and nearly
total loss of the joint function; in particular, the patient presented
with elbow stiffness in slight flexion, severely limited articular
excursion in both active and passive pronation and extension. The
patient underwent both upper and lower limbs radiographs that
showed osteolysis and destructive process of the right elbow and
asymptomatic resorption of both femoral great trochanters more
evident on the left one (Fig. 1). In particular, the right elbow showed
joint space narrowing with loss of articular cartilage, humeral
condyles dysplasia, erosion of both proximal ulna and radius,
palmar angulation of ulnar olecranon resulting in arthrosic defor-
mity with marked signs of hyperostosis and loss of normal articular
contacts (Fig. 2). In a previous radiological assessment performed
3 years before, less extensive hyperostosis and condyles dysplasia
was present with conserved articular contacts and no palmar
angulation of ulna (Fig. 3A); a concurrent CT scan of the region
enabled to show that these bone alterations were associated with
intra- and peri-articular soft tissues edema (Fig. 3B). The mono-
lateral appearance of the deformities could be explained, at least in
part, by right handedness.
Plasma calcium (9.2 mg/dl), phosphorus (3.9 mg/dl), and intact
parathyroid hormone (55 pg/ml) concentrations were normal as
well as plasma 25-OH vitamin D3 levels (27.6 ng/ml); plasma
alkaline-phosphatase concentration and its bone isoenzyme were
normal (respectively, 82 IU/L and 48%) whereas osteocalcin N-
MID levels were low (10.94 pmol/L, normal range 1442); on thecontrary plasma osteoclast marker type-1 collagen C-telopeptide
(CTX-1), and serum matrix metalloproteinase 9 (MMP9) were
elevated, respectively, 0.31 ng/ml (normal values 0.000.30) and3.5 ng/ml (mean SD of a healthy population 0.69 0.13). Thelatter values are consistent with an increase in osteoclast activity
[Lombardi et al., 2008]. These biochemical markers did not sub-
stantially change over a period of almost 7 years.
Bone mineral density, measured with dual energy X-ray absorp-
tiometry (DEXA) at the lumbar spine (L1L4) and femoral necksites, was reduced (0.925 g/cm2, T-score 1.5 and 0.482 g/cm2,T-score 3.3, respectively).
Paolo Sbraccia, M.D., Ph.D., Department of Internal Medicine, University
of Rome Tor Vergata, Via Montpellier, 1, I-00133 Rome, Italy.
Published online 11 October 2010 in Wiley Online Library
How to Cite this Article:Guglielmi V, DAdamo M, DApice MR,
Bellia A, Lauro D, Federici M, Lauro R,
Novelli G, Sbraccia P. 2010. Elbow
deformities in a patient with mandibuloacral
dysplasia type A.
Am J Med Genet Part A 152A:27112713.
2010 Wiley-Liss, Inc. 2711
Several lines of evidence suggest that age-related disease pro-
gression may play a role in the reported bone lesions. First, in our
patient these lesions were absent in the previous skeletal radio-
graphic workup (2002) and only minor alterations were detectable
in 2006 when symptoms firstly occurred. Moreover, progression of
bone deformities in our patient is also evident in hands as is shown
in Figure 4 with progressive resorption of distal and middle
Second, similar but more extensive skeletal changes were recently
described in a Japanese woman with the novel LMNA (A529T)
homozygous mutation, who is in fact the oldest (56-year-old)
MADA patient so far described [Kosho et al., 2007].
FIG. 2. Right elbow X-ray films showing humeral condyles dysplasia (white arrow, A), and palmar angulation of ulnar olecranon (white arrowhead) with
marked signs of hyperostosis (small white arrowheads) (B), and loss of normal articular contacts (open arrowheads) (A,B).
FIG. 3. A: X-rays of right elbow in 2006 showing less extensive
hyperostosis (small white arrowhead) and condyles dysplasia
(white arrow), conserved articular contacts (open arrowhead) and
no palmar angulation of ulna (white arrowhead). B: 2006 CT scan
of the region showing the presence of edema of intra- and peri-
articular soft tissues (white arrows).
FIG. 1. A-P X-ray projection of pelvic bones showing bilateral
resorption of femoral great trochanters, in particular in the left
2712 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Third, analysis of MADA patients fibroblasts showed that the
severity of both unprocessed prelamin A accumulation and chro-
matin disorganization was age related [Filesi et al., 2005].
Skeletal abnormalities are pathognomonic features of MAD
patients; however, such extensive destructive rearrangements of
bone architecture were never reported before in R527H-MADA pa-
tients. Osteolysis indeed is a common feature in laminopathies, being a
well-known characteristic of HutchinsonGilford Progeria syndrome,even more expressed in the non-classical type of progeria that shares
some common features with MADA [Hennekam, 2006]: in fact earlier
descriptions of elbow osteolysis have been reported in patients with
non -classical type of progeria [Rava, 1967; Monu et al., 1990];
osteoporosis is also a feature of atypical Werner syndrome
[Worman et al., 2009]. A more severe and always fatal form of
laminopathy, restrictive dermopathy, also presents with bone abnor-
malities but this type of osteolysis is barely comparable to bone
deformities in MADA patients because of the early lethality of this form.
In MAD, therefore, osteolysis is not confined to the originally
described sites only (hands and clavicula), but it may affect other
skeletal regions. In this light, we believe that efforts should be made
to early detect bone and articular abnormalities by means of more
extensive imaging workup.
In conclusion, we propose to consider osteolysis a more gener-
alized feature of MAD, regarding mostly adult patients, that
nonetheless should be assessed in young patients as well. Such
finding in fact, together with the already known decrease in bone
mineral density, may warrant an early start of some bone metabolic
therapy (such as anti-resorptive agents) in order to prevent or delay
irreversible bone and joint deformities.
Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns J-P, Garg A. 2006. Focal segmental glomerulosclerosis in patients withmandibuloacral dysplasia due to zinc metalloproteinase deficiency. JInvest Med 54:208213.
Filesi I, Gullotta F, Lattanzi G, DApice MR, Capanni C, Nardone AM,Columbaro M, Scarano G, Mattioli E, Sabatelli P, Maraldi NM, Biocca S,Novelli G. 2005. Alterations of nuclear envelope and chromatin organi-zation in mandibuloacral dysplasia, a rare form of laminopathy. PhysiolGenomics 23:150158.
Hennekam RCM. 2006. HutchinsonGilford Progeria syndrome: Reviewof the phenotype. Am J Med Genet Part A 140A:26032624.
Kosho T, Takahashi J, Momose T, Nakamura A, Sakurai A, Wada T,Yoshida K, Wakui K, Suzuki T, Kasuga K, Nishimura G, Kato H,Fukushima Y. 2007. Mandibuloacral dysplasia and a novel LMNAmutation in a woman with severe progressive skeletal changes. Am JMed Genet Part A 143A:25982603.
Lombardi F, Fasciglione GF, DApice MR, Vielle A, DAdamo M, SbracciaP, Marini S, Borgiani P, Coletta M, Novelli G. 2008. Increased release andactivity of matrix metalloproteinase-9 in patients with mandibuloacra