Mandibuloacral dysplasia and a novel <i>LMNA</i> mutation in a woman with severe progressive skeletal changes

Kosho, Tomoki; Takahashi, J.; Momose, Tomoyasu; Nakamura, Akinori; Sakurai, Akihiro; Wada, Takahito; Yoshida, Katsumi; Wakui, Keiko; Suzuki, Takefumi; Kasuga, Kazuo; Nishimura, Gen; Kato, Hiroyuki; Fukushima, Yoshimitsu

doi:10.1002/ajmg.a.31983

Cited by 37 publications

(27 citation statements)

References 16 publications

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“…Similar phenotype combining mandibuloacral dysplasia (MAD), progeroid appearance, and rigid spine muscular dystrophy was caused by the p.R471C homozygous mutation in LMNA [Zirn et al, 2008]. A 56-year-old Japanese woman with MAD, type A lipodystrophy and severe progressive skeletal changes showed the homozygous p.A529T mutation [Kosho et al, 2007]. Cao and Hegele [2003] reported heterozygous mutations p.R527C/p.R471C in a female who initially was thought to have atypical HGPS.…”

Section: Discussionmentioning

confidence: 96%

“…MADA, as FPLD2, is caused by mutations in the LMNA gene (LMNA; OMIM# 150330) encoding the A and C lamins, intermediate filaments of the nuclear envelope. The most common MADA defect is a homozygous missense mutation (p.R527H) in the C-terminal domain of lamins A/C [Novelli et al, 2002;Shen et al, 2003], but different homozygous or compound heterozygous patients have been reported [Cao and Hegele, 2003;Plasilova et al, 2004;Garg et al, 2005;Kosho et al, 2007;Lombardi et al, 2007;Agarwal et al, 2008;Zirn et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

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Mandibuloacral dysplasia type A in childhood

Garavelli

D’Apice

Rivieri

et al. 2009

American J of Med Genetics Pt A

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Mandibuloacral dysplasia type A (MADA) is characterized by growth retardation, postnatal onset of craniofacial anomalies with mandibular hypoplasia, progressive acral osteolysis, and skin changes including mottled pigmentation, skin atrophy, and lipodystrophy. Owing to its slowly progressive course, the syndrome has been recognized in adults, and pediatric case reports are scarce. We present the clinical case of two children in whom the diagnosis of MADA was made at an unusually early age. A 5-year-old boy presented with ocular proptosis, thin nose, and short and bulbous distal phalanges of fingers. A 4-year-old girl presented with round face and chubby cheeks, thin nose, bulbous fingertips, and type A lipodystrophy. In both, a skeletal survey showed wormian bones, thin clavicles, short distal phalanges of fingers and toes with acro-osteolysis. Both children were found to be homozygous for the recurrent missense mutation, c.1580G>A, (p.R527H) in exon 9 of the LMNA gene. Thus, the phenotype of MADA can be manifest in preschool age; diagnosis may be suggested by short and bulbous fingertips, facial features, and lipodystrophy, supported by the finding of acral osteolysis, and confirmed by mutation analysis.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Mandibuloacral dysplasia type A in childhood

Garavelli

D’Apice

Rivieri

et al. 2009

American J of Med Genetics Pt A

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“…They form a meshwork located between the inner nuclear membrane and the chromatin, so they play a fundamental role in the maintenance of the size and shape of the nucleus (7) and in several nuclear processes such as transcription, chromatin organization and DNA replication. Mutations in the LMNA gene can bring about cardiac and skeletal muscle diseases, lipodystrophy and premature ageing phenotypes (8)(9)(10). Mandibuloacral dysplasia (MAD) is also due to a mutation in another gene (i.e.…”

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confidence: 99%

Increased release and activity of matrix metalloproteinase‐9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome

Lombardi

Fasciglione

D’Apice³

et al. 2008

Clinical Genetics

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Sbraccia P, Marini S, Borgiani P, Coletta M, Novelli G. Increased release and activity of matrix metalloproteinase-9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome.Mandibuloacral dysplasia type A (MADA; OMIM 248370), a rare disorder caused by mutation in the LMNA gene, is characterized by post-natal growth retardation, craniofacial and skeletal anomalies (mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, low bone mass and joint contractures), cutaneous changes and partial lipodystrophy. Little is known about the molecular mechanisms by which LMNA mutations produce bone alterations. An altered bone extracellular matrix (ECM) remodelling could play a pivotal role in this disorder and influence part of the typical bone phenotype observed in patients. Therefore, we have focused our investigation on matrix metalloproteinases (MMPs), which are degradative enzymes involved in ECM degradation and ECM remodelling, thus likely contributing to the altered bone mineral density and bone metabolism values seen in five MADA patients. We evaluated the serum levels of several MMPs involved in bone development, remodelling and homeostasis, such as MMP-9, -2, -3, -8 and -13, and found that only the 82 kDa active enzyme forms of MMP-9 are significantly higher in MADA sera compared with healthy controls (n ¼ 16). The serum level of MMP-3 was instead lower in all patients. No significant differences were observed between controls and MADA patients for the serum levels of MMP-2, -8 and -13 and of tissue inhibitor of metalloproteinase 2, a natural inhibitor of MMP-9. Similarly, normal serum levels of tumour necrosis factor alpha (TNF-a), interleukin (IL)-6 and IL-1b were detected. These data suggest a possible involvement of MMP-9 in MADA disease, underlying the potential use in diagnosis and therapy.

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“…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]. Third, analysis of MADA patients fibroblasts showed that the severity of both unprocessed prelamin A accumulation and chromatin disorganization was age related [Filesi et al, 2005].…”

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confidence: 55%

“…We describe elbow deformities in a previously characterized male 43-year-old patient, with homozygous LMNA missense mutation (R527H) [Novelli et al, 2002], who is the second oldest studied MADA patient [Kosho et al, 2007].…”

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confidence: 99%

Elbow deformities in a patient with mandibuloacral dysplasia type A

Guglielmi

D'Adamo

D’Apice

et al. 2010

American J of Med Genetics Pt A

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Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial 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 heterogeneity 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 mutation (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, deformation 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 deformity 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 monolateral 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-te...

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Mandibuloacral dysplasia and a novel LMNA mutation in a woman with severe progressive skeletal changes

Cited by 37 publications

References 16 publications

Mandibuloacral dysplasia type A in childhood

Mandibuloacral dysplasia type A in childhood

Increased release and activity of matrix metalloproteinase‐9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome

Elbow deformities in a patient with mandibuloacral dysplasia type A

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