Mandibuloacral dysplasia (MAD) is a rare genetic disorder characterized by distinctive skeletal abnormalities, metabolic issues, and skin changes, often linked to pathogenic variants in the LMNA gene, which encodes lamin A/C. This study investigates a specific founder mutation within a Turkish cohort and explores its impact on phenotypic expressivity. We conducted a comprehensive analysis involving genetic testing for LMNA variants in patients diagnosed with MAD. Clinical evaluations documented a wide range of phenotypic features, including facial dysmorphism, skeletal anomalies, and metabolic abnormalities. We also collected family histories to assess inheritance patterns and potential environmental influences. Our findings identified a common founder mutation in the LMNA gene among the cohort, which was present in a significant percentage of participants. Notably, phenotypic expressivity varied significantly, with some individuals exhibiting classic MAD features, while others showed atypical manifestations, such as additional endocrine disorders and variable severity of skeletal anomalies. This variability underscores the complexity of the genotype-phenotype relationship. This study highlights the significance of the founder mutation in LMNA and its diverse phenotypic outcomes in MAD. Our results contribute to the understanding of how genetic mutations can lead to a spectrum of clinical presentations, emphasizing the necessity for personalized clinical approaches in managing this condition. Further research is warranted to elucidate the underlying mechanisms of phenotypic variability and to improve diagnostic and therapeutic strategies.

Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome.

To report the case of a girl presenting a severe phenotype of mandibuloacral dysplasia type A (MADA) characterized by prominent osteolytic changes and ectodermal defects, associated with a rare homozygous LMNA missense mutation (c.1579C>T). A 6-year-old girl was evaluated during hospitalization exhibiting the following dysmorphic signs: subtotal alopecia, dysmorphic facies with prominent eyes, marked micrognathia and retrognathia, small beaked nose, teeth crowding and thin lips, generalized lipodystrophy, narrow and sloping shoulders, generalized joint stiffness and bone reabsorption in the terminal phalanges. In dermatological examination, atrophic skin, loss of cutaneous elasticity, hyperkeratosis, dermal calcinosis, and hyperpigmented and hypochromic patches were observed. Radiology exams performed showed bilateral absence of the mandibular condyles, clavicle resorption with local amorphous bone mass confluence with the scapulae, shoulder joints with subluxation and severe bone dysplasia, hip dysplasia, osteopenia and subcutaneous calcifications. MADA is a rare autosomal recessive disease caused by mutations in LMNA gene. It is characterized by craniofacial deformities, skeletal anomalies, skin alterations, lipodystrophy in certain regions of the body and premature ageing. Typical MADA is caused by the p.R527H mutation in the LMNA gene. However, molecular analysis performed from oral epithelial cells obtained from the patient showed the rare mutation c.1579C>T, p. R527C in the exon 9 of LMNA. This is the sixth family identified with this mutation described in the literature. Relatar o caso de uma jovem que apresentava um fenótipo grave de displasia mandibuloacral tipo A (MADA) caracterizado por alterações osteolíticas proeminentes e defeitos ectodérmicos, associados a uma rara mutação homozigótica missense no gene LMNA (c.1579C>T). Uma menina de seis anos foi avaliada durante hospitalização apresentando os seguintes sinais dismórficos: alopecia subtotal, fácies dismórfica com olhos proeminentes, micrognatia e retrognatia acentuada, nariz pequeno e adunco, dentes apinhados e lábios finos, lipodistrofia generalizada, ombros estreitos e inclinados, rigidez articular e reabsorção óssea nas falanges terminais. Ao exame dermatológico, observou-se pele atrófica, perda da elasticidade cutânea, hiperceratose, calcinose dérmica e manchas hiperpigmentadas e hipocrômicas. Exames radiológicos realizados mostraram ausência de côndilos mandibulares bilaterais, reabsorção da clavícula com massa óssea amorfa local confluindo com as escápulas, articulações do ombro com subluxação e displasia óssea severa, com displasia coxofemoral, osteopenia e calcificações subcutâneas. MADA é uma doença autossômica recessiva rara causada por mutações no gene LMNA. Caracteriza-se por deformidades craniofaciais, anomalias esqueléticas, alterações cutâneas, lipodistrofia em determinadas regiões do corpo e envelhecimento precoce. MADA típica é causada pela mutação p.R527H no gene LMNA. No entanto, a análise molecular realizada com células epiteliais orais obtidas da paciente mostrou a mutação rara c.1579C>T, p. R527C no exon 9 do gene LMNA. Esta é a sexta família identificada com essa mutação descrita na literatura.

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with "mandibuloacral dysplasia type A" (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype-phenotype correlations.

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes.