RESEARCH LETTER

Elbow Deformities in a Patient With MandibuloacralDysplasia Type AValeria Guglielmi,1 Monica D’Adamo,1 Maria Rosaria D’Apice,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.,

2003].

Thus far, several mutations in LMNA gene have been reported in

23 patients (type A MAD—MADA) while only four patients have

been reported with ZMPSTE24 mutations (type B MAD—MADB)

[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 14–42); on the

contrary 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 0.00–0.30) and

3.5 ng/ml (mean� SD of a healthy population 0.69� 0.13). The

latter 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 (L1–L4) and femoral neck

sites, 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

(wileyonlinelibrary.com)

DOI 10.1002/ajmg.a.33700

How to Cite this Article:Guglielmi V, D’Adamo M, D’Apice 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:2711–2713.

� 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

phalanges.

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

one.

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 Hutchinson–Gilford 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.

REFERENCES

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 54:208–213.

Filesi I, Gullotta F, Lattanzi G, D’Apice 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 23:150–158.

Hennekam RCM. 2006. Hutchinson–Gilford Progeria syndrome: Reviewof the phenotype. Am J Med Genet Part A 140A:2603–2624.

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:2598–2603.

Lombardi F, Fasciglione GF, D’Apice MR, Vielle A, D’Adamo M, SbracciaP, Marini S, Borgiani P, Coletta M, Novelli G. 2008. Increased release andactivity of matrix metalloproteinase-9 in patients with mandibuloacraldisplasia type A, a rare premature ageing syndrome. Clin Genet74:374–383.

Monu JUV, Benka-Coker LBO, Fatunde Y. 1990. Hutchinson-GilfordProgeria syndrome in siblings. Skeletal Radiol 19:585–590.

Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’Apice MR,Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, PallottaR, Scarano G, Dallapiccola B, Merlini L, Bonne G. 2002. Mandibuloacraldysplasia is caused by a mutation in LMNA encoding lamin A/C. Am JHum Genet 71:426–431.

Rava G. 1967. Su un nucleo familiare di progeria. Minerva Med58:1502–1509.

Shackleton S, Smallwood DT, Clayton P, Wilson LC, Agarwal AK, Garg A,Trembath RC. 2005. Compound heterozygous ZMPSTE24 mutationsreduce prelamin A processing and result in a severe progeroid phenotype.J Med Genet 42:e36.

Simha V, Garg A. 2002. Body fat distribution and metabolic derange-ments in patients with familial partial lipodystrophy associatedwith mandibuloacral dysplasia. J Clin Endocrinol Metab87:776–785.

Simha V, Agarwal AK, Oral EA, Fryns JP, Garg A. 2003. Genetic andphenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy. J Clin Endocrinol Metab 88:2821–2824.

Worman HJ, Fong LG, Muchir A, Young SG. 2009. Laminopathies and thelong strange trip from basic cell biology to therapy. J Clin Invest119:1825–1836.

FIG. 4. Comparison of left hand X-rays showing progressive middle

and distal phalanges resorption.

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