Restrictive Dermopathy (RD, OMIM #275210) is an ultra-rare, lethal genodermatosis caused by defects in lamins and related proteins. RD is caused by biallelic pathogenic variants in ZMPSTE24, which encodes zinc metallopeptidase ZMPSTE24, an enzyme essential for processing prelamin A, the precursor of lamin A. While null variants leading to a total loss of prelamin A processing have been related to neonatally lethal RD, variants preserving residual prelamin A processing function cause an allelic disorder called Mandibuloacral Dysplasia Type B (MAD-B). RD is characterized by taut translucent skin, visible superficial vessels, joint contractures, and dysmorphic features, with death usually occurring within the first month of life. Cardiac anomalies, including ASD and PDA, have been reported in a few patients, most of whom were not genetically confirmed, and transposition of the great arteries (TGA) has been described only once, also without molecular confirmation. We report a patient with restrictive dermatopathy (RD) presenting with double outlet right ventricle (DORV) and pulmonary valve atresia which have not been previously reported in association with RD. Exome Sequencing (ES) was performed, revealing a novel homozygous splice-site variant in ZMPSTE24 (c.1203 + 1G>T). Segregation analysis was performed in the mother and two siblings. To our knowledge, DORV has not previously been reported in an RD patient. This case expands the genotypic spectrum of RD and suggests a possible link with complex cardiac malformations.

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.

Individuals with homozygous laminA/C p.R527C mutations manifest a severe form of Mandibuloacral dysplasia-(MAD) and exhibit overlapping progeroid symptoms, for which the underlying molecular pathology remains unknown. Herein, it is shown that MAD patients achieved inflammaging with different pro-inflammatory cytokines compared to progeria-(HGPS) patient. Characterization of MAD iPSC-derived Mesenchymal stem cells (MAD-iMSC) uncovers deregulated mitochondrial Ca+2 as the primary cause of inflammaging, mediated through inflammasome formation rather than the cGAS-STING pathway. Moreover, MAD-iMSCs extracellular vesicles (EVs) can also upregulate mitochondrial Ca+2 in healthy cells. This deregulated Ca+2 homeostasis is indirectly mediated by mitochondrial calcium mediator, signal transducer, and activator of transcription-3 (STAT3), situated on the mitochondrial associated membrane (MAM). Inflammaging is mitigated by various FDA-approved MAM-STAT3 upstream inhibitors, such as (Tocilizumab) or by correcting R527C mutation with CRISPR/CAS9. These results provide new insights into MAD disease and propose targeting defective mitochondrial Ca+2 homeostasis as a promising therapy for reversing immunosenescence.

Restrictive dermopathy (RD) is a rare, lethal, congenital autosomal recessive laminopathy syndrome characterized by generalised tight translucent skin, dysmorphic facies, arthrogryposis multiplex congenita, and pulmonary hypoplasia. It is caused by mutations in either ZMPSTE24 or LMNA. Variants in these genes, which disrupt the production of lamin A, and hence the structural integrity of the nuclear envelope, can also cause survivable syndromes such as mandibuloacral dysplasia (MAD). We report the first son of non-related Caucasian parents delivered via emergency LSCS at 34 weeks following preeclampsia, gestational diabetes and polyhydramnios. Extraction was difficult due to arthrogryposis. At birth (weight 1.65 kg), he showed the typical features of RD. Genetic testing revealed a homozygous pathogenic ZMPSTE24 frameshift variant c.1085dup p. (Leu362PhefsTer19) previously reported in mandibuloacral dysplasia (Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 2003;12:1995-2001). Parents were heterozygous carriers. The baby received palliative care and died on day 2. The longest survival in RD is 120 days, in contrast to other laminopathies. Similar or identical mutation within the LMNA gene produces varied phenotypes which expands the spectrum. Currently, there is no curative therapy for RD. Our main aim to diagnose this condition is to offer counselling, genetic testing for future pregnancies, prevent unnecessary interventions and support the family through compassion and dignity.

Mandibuloacral dysplasia type A (MADA) is a rare progeroid syndrome associated with mutations in the Lamin A/C (LMNA) gene, primarily affecting skeletal, cutaneous, and adipose tissues. While certain LMNA gene mutations are known to cause cardiomyopathy and conduction system disease, severe early-onset calcific valvular heart disease is not conventionally considered a typical feature of MADA. This report describes two brothers from a consanguineous Han Chinese family who presented with classical MADA phenotypes alongside severe, early-onset cardiac valvular calcification. Genetic investigation revealed that both affected brothers carried a homozygous missense mutation, c.785A > G (p.Glu262Gly), in the LMNA gene. The elder brother, aged 41, successfully underwent transcatheter aortic valve implantation (TAVI) due to severe aortic valve stenosis. This finding represents the first association, to our knowledge, between the homozygous LMNA c.785A > G (p.Glu262Gly) mutation and significant severe early-onset cardiac valvular calcification manifesting as a prominent feature within the MADA phenotype, thus expanding the clinical spectrum associated with MADA and this specific LMNA variant. This case highlights a potentially underrecognized cardiovascular manifestation in MADA patients and underscores the importance of comprehensive cardiac assessment in affected individuals, particularly those from consanguineous families.