Elbow deformities in a patient with mandibuloacral dysplasia type A

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    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


    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).

    *Correspondence to:

    Paolo Sbraccia, M.D., Ph.D., Department of Internal Medicine, University

    of Rome Tor Vergata, Via Montpellier, 1, I-00133 Rome, Italy.

    E-mail: sbraccia@med.uniroma2.it

    Published online 11 October 2010 in Wiley Online Library


    DOI 10.1002/ajmg.a.33700

    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



  • 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.


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    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.

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    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