Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.

Fontaine progeroid syndrome (FPS, OMIM 612289) is a recently identified genetic disorder stemming from pathogenic variants in the SLC25A24 gene, encoding a mitochondrial carrier protein. It encompasses Gorlin-Chaudry-Moss syndrome and Fontaine-Farriaux syndrome, primarily manifesting as craniosynostosis with brachycephaly, distinctive dysmorphic facial features, hypertrichosis, severe prenatal and postnatal growth restriction, limb shortening, and early aging with characteristic skin changes, phalangeal anomalies, and genital malformations. All known occurrences of FPS have been postnatally observed until now. Here, we present the first two prenatal cases identified during the second trimester of pregnancy. While affirming the presence of most postnatal abnormalities in prenatal cases, we note the absence of a progeroid appearance in young fetuses. Notably, our reports introduce new phenotypic features like encephalocele and nephromegaly, which were previously unseen postnatally. Moreover, paternal SLC25A24 mosaicism was detected in one case. We present the initial two fetal instances of FPS, complemented by thorough phenotypic and genetic assessments. Our findings expand the phenotypical spectrum of FPS, unveiling new fetal phenotypic characteristics. Furthermore, one case underscores a potential novel inheritance pattern in this disorder. Lastly, our observations emphasize the efficacy of exome/genome sequencing in both prenatal and postmortem diagnosis of rare polymalformative syndromes with a normal karyotype and array-based comparative genomic hybridization (CGH).

Fontaine progeroid syndrome (FPS) is an autosomal dominant condition caused by pathogenic variants in the SLC25A24 gene. Eleven cases have been described in the literature, with early lethality in some. We discuss the clinical course of a patient from birth until his death at 7 months. SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described. The diagnosis of SLC25A24 Fontaine progeroid syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SLC25A24 identified by molecular genetic testing. Treatment of manifestations: Management, which is largely symptomatic, may be performed by specialists in multiple disciplines, including a craniofacial clinic (involving plastic surgery, neurosurgery, and otolaryngology), cardiology, pulmonology, gastroenterology, and clinical genetics. Some students may benefit from an individualized education plan through their school. Surveillance: Routine evaluation to assess development of new manifestations and response to ongoing management. Agents/circumstances to avoid: Contact sports and isometric exercise may need to be restricted if cranial anomalies and/or aortic dilatation are present. SLC25A24 Fontaine progeroid syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo SLC25A24 pathogenic variant. However, given a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism, prenatal and preimplantation genetic testing may be considered.

Aging is a physiological process that is in part genetically determined. Some of the signs and symptoms of aging also occur prematurely in Mendelian disorders. Such disorders are excellent sources of information of underlying mechanisms for these components of aging, and studying these may allow detection of pathways that have not yet considered in detail in physiological aging. Here I define the clinical characteristics that constitute aging and propose that at least 40% of aging signs and symptoms should be present before an entity should be tagged as progeroid. A literature search using these characteristics yields 17 entities that fulfill this definition: Hutchinson-Gilford progeria, mandibulo-acral dysplasia, Nestor-Guillermo progeria, Werner syndrome, Cockayne syndrome, cutis laxa progeroid, Penttinen progeroid syndrome, Mandibular underdevelopment, Deafness, Progeroid features, Lipodystrophy, Fontaine progeroid syndrome, SHORT syndrome, Wiedemann-Rautenstrauch syndrome, Mulvihill-Smith syndrome, dyskeratosis congenita, Marfan syndrome lipodystrophy type, Warburg-Cinotti syndrome, Lessel syndrome and Bloom syndrome. The presenting and main characteristics of these entities are indicated briefly. Their pathophysiology is not complete pathophysiology is reviewed but only the pathophysiology of the premature aging characteristics of this series of entities is compared to the known mechanisms ("Hallmarks") of physiological aging as summarized in the review paper by Lopez-Otin and colleagues. Although many causative genes have not been studied fully for all known aging mechanisms the comparison demonstrates that additional mechanisms must play a role to explain the aging characteristic in some of the progeroid entities of the progeroid entities, and possibly also in physiological aging.