Endocrinological manifestations in RASopathies

Tamburrino, Federica; Scarano, Emanuela; Schiavariello, Concetta; Perri, Annamaria; Pession, Andrea; Mazzanti, Laura

doi:10.1002/ajmg.c.32013

Cited by 5 publications

(4 citation statements)

References 77 publications

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“…To date, over 20 genes have been associated with RASopathies in scientific research [ 27 ]. The RAS pathway controls the progression of cell cycles, cellular expansion, reproduction, specialization, and metabolism [ 2 , 28 , 29 ]. Additionally, it has a vital function in the establishment and preservation of equilibrium in various tissue types.…”

Section: Discussionmentioning

confidence: 99%

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Liu,

Hu,

Chen

et al. 2023

Am J Case Rep

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Patient: Female, 7-year-old Final Diagnosis: Noonan-like syndrome with loose anagen hair Symptoms: Thrombocytopaenia and anaemia Clinical Procedure: — Specialty: Genetics • Hematology • Pediatrics and Neonatology Objective: Rare disease Background: RASopathies involve mutations in genes that encode proteins participating in the RAS-mitogen-activated protein kinase pathway and are a collection of multisystem disorders that clinically overlap. Variants in the SHOC2 gene have been reported in Noonan-like syndrome, which include distinct facial features, short stature, congenital cardiac defects, developmental delays, bleeding disorders, and loose anagen hair. This report is of a 7-year-old girl with the c.4A>G (p.Ser2Gly) variant of the SHOC2 gene, consistent with Noonan-like syndrome, with loose anagen hair, presenting with thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. Case Report: The child had a medical history of 7 hospitalizations at our institution. At the age of 2 months, she underwent surgical correction for ventricular and atrial septal defects. At the age of 2 years, tonsil and adenoid removal surgery was performed, followed by surgery for otitis media at age 5 years. At 7 years, she was hospitalized for the simultaneous occurrence of thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. The patient displayed short stature and mild intellectual disability. Notable facial features included sparse hair, mild frontal bossing, and low-set ears. Antinuclear antibody levels demonstrated a significant gradual shift. Through trio whole-exome sequencing, a c.4A>G (p.Ser2Gly) variation in the SHOC2 gene was identified. Conclusions: Given the clinical information and genetic testing results, the patient’s condition appeared to closely be a type of RASopathy. This report has highlighted the importance of physical, developmental, and genetic testing in children presenting with dysmorphism, developmental delay, and hematological abnormalities.

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Section: Discussionmentioning

confidence: 99%

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Liu,

Hu,

Chen

et al. 2023

Am J Case Rep

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“…In addition, in a group of 12 genetically confirmed NS subjects who reached final height, Tamburrino et al. showed a delay in onset by about 6 months in NS subjects compared to the general population and that pubertal growth had a lowered peak, in particular in males ( 15 , 16 ).…”

Section: Characteristics Of Puberty In Noonan Syndromementioning

confidence: 98%

“…Most familial cases that have been reported have shown an overrepresentation of affected mothers. Although males appear to have reduced fertility, male transmission is well described and not uncommon ( 16 , 17 , 25 – 29 ).…”

Section: Vertical Transmission In Noonan Syndrome and Role Of Ras Pat...mentioning

confidence: 99%

Abnormalities of pubertal development and gonadal function in Noonan syndrome

et al. 2023

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BackgroundNoonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.MethodsIn this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.ConclusionsAccording to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.

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“…Short stature is a cardinal feature of NS, and its severity varies according to the genotype [4]. It is also a common feature in other rasopathies, particularly in CFCS, CS, and NSLAH [5].…”

Section: Introductionmentioning

confidence: 99%

Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment

Carcavilla,

Cambra,

Santomé

et al. 2023

JCM

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Molecular study has become an invaluable tool in the field of RASopathies. Treatment with recombinant human growth hormone is approved in Noonan syndrome but not in the other RASopathies. The aim of this study was to learn about the molecular base of a large cohort of patients with RASopathies, with particular emphasis on patients with pathogenic variants in genes other than PTPN11, and its potential impact on rGH treatment indication. We reviewed the clinical diagnosis and molecular findings in 451 patients with a genetically confirmed RASopathy. HRAS alterations were detected in only 2 out of 19 patients referred with a Costello syndrome suspicion, whereas pathogenic variants in RAF1 and SHOC2 were detected in 3 and 2, respectively. In 22 patients referred with a generic suspicion of RASopathy, including cardiofaciocutaneous syndrome, pathogenic alterations in classic Noonan syndrome genes (PTPN11, SOS1, RAF1, LZTR1, and RIT1) were found in 7 patients and pathogenic variants in genes associated with other RASopathies (HRAS, SHOC2, and PPPCB1) in 4. The correct nosological classification of patients with RASopathies is critical to decide whether they are candidates for treatment with rhGH. Our data illustrate the complexity of differential diagnosis in RASopathies, as well as the importance of genetic testing to guide the diagnostic orientation in these patients.

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Endocrinological manifestations in RASopathies

Cited by 5 publications

References 77 publications

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant

Abnormalities of pubertal development and gonadal function in Noonan syndrome

Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment

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