Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis

Abstract

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

The E262K mutation in Lamin A links nuclear proteostasis imbalance to laminopathy‐associated premature aging

“…Interestingly, the c.784G>A base substitution in the LMNA gene, resulting in a non‐conservative E262K missense mutation in the LMNA protein (Figure 1d). The E262K mutation had also been previously reported in an individual with atypical progeroid syndrome and lipodystrophy (Yukina et al, 2021). The in silico algorithms predicted this mutation as damaging and pathogenic (Figure S2).…”

Skeletal alterations in lipodystrophy

“…Interestingly, laminopathies can also lead to diseases with features of accelerated aging, named progerias (from the Greek words πρό, "premature" and γέρων, "old"). These conditions, associated with LMNA mutations, are recognized in different progeroid syndromes, both typical (Hutchinson-Gilford progeria syndrome, type A mandibulo-acral dysplasia, restrictive dermopathy) and atypical forms, including Werner syndrome [9,12] . The possible involvement of skeletal alterations in these conditions might be due, among other reasons, to the fact that lamin A/C is an intermediate protein from the nuclear lamina, encoded by the LMNA gene, that plays a key role in facilitating the mechano-signaling of cytoskeletal from cell membrane into the nucleus.…”

“…Moreover, individuals affected by progeroid syndromes, either typical or atypical, show significant skeletal alterations associated with adipose tissue loss and other clinical and metabolic alterations [9,12,21] . An experimental animal model, i.e., fatfree (FF) mice mimicking Berardinelli-Seip patients, showed potent osteoblastic activity, leading to increased trabecular and cortical bone volume.…”

“…In some patients, these complications can lead to diabetic nephropathy and retinopathy, acute pancreatitis due to severe hypertriglyceridemia and chylomicronemia, liver cirrhosis, and early-onset cardiovascular disease. Congenital lipodystrophies are very rare and can be apparent at birth, in the case of classic congenital generalized lipodystrophy, the progeroid neonatal forms, and Keppen-Lubinski syndrome [7] , while in other forms, such as partial lipodystrophy forms or mandibulo-acral dysplasia, the loss of adipose tissue can manifest itself later in life [1,8,9] . As indicated, the loss of adipose tissue can be generalized, with almost total loss of adipose tissue in the body, or affect only some areas of the body.…”

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

“…Atypical progeroid syndrome (APS) is another type of progeria from LMNA mutation. APS is very rare, and until now, 69 patients with LMNA mutation have been reported worldwide (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). It is characterized by not having an accumulation of the Lamin A precursors (14,15) and is caused by heterozygous LMNA mutations other than c.1924C > T. The onset of APS symptoms is relatively late, and the life span of APS patients is generally longer than those of HGPS (12,14,15).…”