ESPE2023 Poster Category 1 Growth and Syndromes (75 abstracts)
CEP57 variant associated with MVA2 syndrome in two Moroccan brothers
Salvatore Recupero 1,2 , Rossella Mascaro 1 , Monica Palmoni 1 , Silvia Meroni 1 , Carmen Bucolo 1 , Martina Finamore 1 , Chiara Ferri 1 , Alessia Rizzi 1 , Anna Lia Magnacavallo 1 , Maria Grazia Patricelli 3 , Orsetta Zuffardi 4 , Graziano Barera 1 & Gabriella Pozzobon 1
1Department of Pediatrics, Endocrine Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. 2San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. 3Division of Genetics and Cell Biology and Laboratory of Clinical Molecular Biology and Cytogenetics, Unit of Genomics for Human Disease Diagnosis, IRCCS San Raffaele Scientific Institute, Milan, Italy. 4Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, Pavia, Italy
Mosaic variegated aneuploidy (MVA) syndrome represents a rare autosomal recessive disease characterized by aneuploidies with gain and loss of multiple chromosomes. We describe case of two Moroccan brothers with MVA2, due to CEP57 mutations. Patients are 17 and 13-year-old male siblings of a Moroccan healthy consanguineous couple. Oldest brother was delivered at 35 gestational weeks after IGR diagnosis, small for gestational age (SGA, 1300 grams, -3 SDS). Younger patient’s delivery was 38 gestational weeks and he also resulted SGA (2165 grams, -2.4 SDS). Siblings were evaluated for marked growth delay (<-4 SDS, genetic target -1.32 SDS). Physical examination showed prominent forehead with frontal bossing, sparse hair, dolichocephaly, triangular face, simple low-set ears and broad nasal tip. Additional features included mild rhizomelic limb shortening, diffuse café-au-lait spots, amelogenesis imperfecta, bilateral cryptorchidism (surgically corrected) and mild psychomotor retardation. Older sibling presented pituitary gland hypoplasia without GH deficiency at specific tests, IGF-1 stably over normal limits (>> 2 SDS). During follow-up marked growth delay with reduced growth velocity persisted, he showed insulin resistance requiring metformin, hypertriglyceridemia and liver steatosis; furthermore, partial hypergonadotropic hypogonadism and ultrasound dysthyroidism were detected, not requiring specific therapies. Younger patient presented partial GH deficiency with pituitary hypoplasia, IGF-1 levels significantly increased for age (>> 2 SDS). Partial hypergonadotropic hypogonadism, isolated thyrotropin elevation and insulin resistance, requiring metformin, were similarly identified. No GH therapy was administered in both patients for IGF-1 levels and unknown neoplastic risk. According to clinical features, 100-metaphase chromosome evaluation from lymphocyte cultures was performed, showing in both patients a male karyotype with several chromosomal aneuploidies and multiple trisomies; array-CGH, gene sequencing of IGF1R and BUB1B genes were negative. WES analysis revealed in both patients a homozygous frameshift loss of function mutation in CEP57 gene, related to MVA2. Parents were both carriers of identified mutation. Only 13 patients with pathogenic CEP57 variant have been previously described. Our patients presented hallmarks of MVA2 phenotype: prenatal growth problems, skeletal abnormalities, typical facial features, intellectual disability. Furthermore, our siblings showed partial hypergonadotropic hypogonadism and insulin resistance, which apparently were not previously described in MVA2. MVA1 and MVA3 variants are commonly associated to increased risk of childhood malignancies (rhabdomyosarcoma, Wilms tumor), but neoplastic lesions have not been observed in reported cases (oldest one was 29 years old) and in our patients. A longer follow-up and further studies occur to correctly clarify tumor risk and genotype-phenotype correlation in MVA2 patients.
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