Identification of pathogenic variants in three Chinese patients with McCune-Albright syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS).@*METHODS@#Three children who had respectively presented at Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members.@*RESULTS@#The proband from family 1 was found to harbor a heterozygous c.601C>T (p.R201C) missense variant in exon 8 of the GNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c.602G>A (p.R201H) missense variant in exon 8 of the GNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees.@*CONSLUSION@#WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.

Caracterización clínica de pacientes chilenos con displasia fibrosa/síndrome de McCune-Albright / Clinical features of Chilean patients with Fibrous Dysplasia/McCune-Albright Syndrome

BACKGROUND: Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is characterized by a spectrum of manifestations that may include fibrous dysplasia of bone and multiple endocrinopathies. AIM: To describe the clinical spectrum, the study and follow-up of patients with FD/MAS cared at our institution. MATERIAL AND METHODS: Review of medical records of 12 pediatric and adult patients (11 women) who met the clinical and genetic diagnostic criteria for FD/ MAS. RESULTS: The patients' mean age at diagnosis was 4.9 ± 5.5 years. The most common initial clinical manifestation was peripheral precocious puberty (PPP) in 67% of patients and 75% had café-au-lait spots. Fibrous dysplasia was present in 75% of patients and the mean age at diagnosis was 7.9 ± 4.7 years. Ten patients had a bone scintigraphy, with an age at the first examination that varied between 2 and 38 years of age. The most frequent location of dysplasia was craniofacial and appendicular. No patient had a recorded history of cholestasis, hepatitis, or pancreatitis. In four patients, a genetic study was performed that was positive for the pathogenic variant of guanine nucleotide binding protein, alpha stimulating (GNAS). CONCLUSIONS: These patients demonstrate the variable nature of the clinical presentation and study of FD/MAS. It is essential to increase the index of diagnostic suspicion and adherence to international recommendations.

Síndrome de Albrigth-Mccune Sternberg: reporte de un caso y revisión de la literatura / Albright-Mccune Sternberg syndrome: case report and literature review

El síndrome de Albright-McCune Sternberg (SAMS) es un desorden raro que se origina de una mutación del gen GNAS1. Se caracteriza por presentar un fenotipo típico, el cual incluye fibrodisplasia (FD) poliostótica, pubertad precoz (PP), pigmentaciones café au lait (café con leche) junto con otras endocrinopatías. La presente investigación trata de una paciente femenina de 22 años de edad con SAMS la cual presenta algunos signos y síntomas del síndrome tales como: FD poliostótica, pigmentaciones color café con leche en la piel, PP e hipotiroidismo. Acudió por dolor a nivel de las encías inferiores producto de un aumento óseo bimaxilar, inicia su enfermedad actual en mayo de 2013 presentando dolor a nivel de mucosa gingival inferior, localizado, punzante, de intensidad moderada, el cual se agrava ante la masticación y dura hasta el cese del estimulo. La FD fue diagnosticada posterior a la realización de una biopsia de tejido óseo y estudios radiográficos, la paciente presentó metrorragia a los nueve meses de edad el cual se repitió a los cinco años y persistió de manera intermitente hasta los veinte años de edad donde fue diagnosticada con ovarios poliquísticos por lo cual se le prescribió etinilestradiol y acetato de ciproterona. Aunque el SAMS generalmente cursa con una hiperfunción endocrina la paciente tiene un diagnóstico de hipotiroidismo por lo cual está bajo tratamiento con levotiroxina.

The Albright-McCune Sternberg syndrome (AMSS) is a rare disorder that arises from a mutation of the GNAS1 gene. It is characterized by a typical phenotype, which includes polyostotic fibrous dysplasia (FD), precocious puberty (PP), cafe-au-lait pigmentations and other endocrinopathies. The following research is about a 22 year old female patient with SAMS which presents some signs and symptoms of the syndrome such as polyostotic FD, pigmentation of the skin, PP and hypothyroidism. She attended by pain in the lower gum product of increased bimaxillary volume it began in may 2013 having pain in lower gingiva localized, throbbing, of moderate intensity, which is exacerbated by chewing and lasts until the cessation of the stimulus. The FD was diagnosed after performing a bone biopsy and radiographic studies, the patient had metrorrhagia at nine months of age which was repeated at five years and persisted intermittently until twenty years where he was diagnosed with polycystic ovaries so was prescribed ethinylestradiol and cyproterone acetate. Although the AMSS usually occurs with endocrine hyperfunction the patient has a diagnosis of hypothyroidism which is treated with levothyroxine.

Hipertireoidismo relacionado à síndrome de McCune Albright: relato de dois casos e revisão da literatura / Hyperthyroidism related to McCune-Albright syndrome: report of two cases and review of the literature

INTRODUÇÃO: A síndrome de McCune Albright é uma doença rara, clinicamente definida pela combinação de displasia fibrosa poliostótica, manchas café-com-leite e endocrinopatias com hiperfunção, como puberdade precoce, hipertireoidismo, acromegalia e outras. A fisiopatologia biomolecular baseia-se em uma mutação ativadora do gene para a subunidade alfa da proteína de membrana Gs, que estimula a produção intracelular de AMPc, conferindo secreção autônoma à glândula em particular. A glândula tireóide é freqüentemente envolvida nesta doença, sendo o hipertireoidismo a segunda endocrinopatia mais comum após a puberdade precoce. OBJETIVO: Realizar uma revisão da literatura no período de 1937 a 1997, incluindo nossa casuística, e discutir o tratamento utilizado para o hipertireoidismo nesta síndrome. RESULTADOS: Do total de 85 casos, em 26 com hipertireoidismo se descreve o tipo de tratamento utilizado. Entre esses, 15 foram submetidos à cirurgia (tireoidectomia total), seis foram submetidos à iodoterapia e cinco foram submetidos a tratamento com drogas antitireoidianas (DAT - propiltiuracil, carbimazol ou metimazol), pois em alguns houve associação dos tratamentos citados anteriormente. CONCLUSÃO: A síndrome de McCune-Albright é uma doença rara, que inclui displasia fibrosa poliostótica, manchas café-com-leite e endocrinopatias com hiperfunção. Os casos acompanhados com hipertireoidismo são inicialmente tratados clinicamente com DAT, porém a ablação cirúrgica ou com radioiodoterapia é a opção definitiva mais indicada.

INTRODUCTION: McCune-Albright syndrome is a sporadic disease clinicaly characterized by polyostotic fibrous dysplasia, "café-au-lait" cutaneous spots and hyperfunctional endocrinopathies, such as precocious puberty, hyperthyroidism, acromegaly and others. The biologic physiopathology of the disease is based on an activating mutation of the gene for the Gs protein which mediates the activation of adenyl cyclase and subsequent gland autonomous secretion. The thyroid gland is usually involved in this disease, being hyperthyroidism the second most common endocrinopathy seen after precocious puberty. OBJECTIVE: Revision of the literature since 1937 to 1997, adding our casuistic and discussing the adequate treatment for the hyperthyroidism in the syndrome. RESULTS: Among 85 cases identified with the syndrome, hyperthyroidism treatment was described in 26 of them. Fifteen were submitted to surgery (total thyroidectomy), 6 were submitted to iodotherapy and 5 were treated with antithyroid drugs (ATD - propylthiouracil, carbimazole or methimazole). In some cases, treatment association was done. CONCLUSION: McCune-Albright syndrome is a rare disease, combining polyostotic fibrous dysplasia, "café-au-lait" cutaneous spots and hyperfunctional endocrinopathies. Cases with hyperthyroidism are treated iniatially clinically, but definitive ablation with surgery or radioiodine treatment is the most indicated option.

Estudio clínico molecular de pacientes chilenas con síndrome de McCune-Albright / Clinical and molecular study of Chilean patients with McCune-Albright Syndrome

Background: McCune-Albright Syndrome (MAS) is characterized by precocious puberty, "cafe au lait" skin lesions and polyostotic fibrous dysplasia. It is caused by 4 post-zygotic mutations of Gas protein with a mosaic distribution. Aim: To describe the clinical presentation and to investigate the presence of the Arg by his substitution (R201H) in 14 girls with MAS. Patients and methods: We performed a clinical analysis of the patients and specific allele PCR in DNA obtained from leukocytes. Results: Twelve of 14 patients presented with precocious puberty, one with cyclical vaginal bleeding and one with pathological bone fractures. Eight girls had polyostotic fibrous dysplasia, one had hyperthyroidism, four had pathological fractures, ten had ovarian cysts, six had breast hyperpigmentation and ten had "cafe au lait" skin lesions. We detected the R2O1H mutation in 10 of 14 patients. We found no difference in the severity of symptoms or in the age of presentation between the patients with and without the mutation. Conclusions: The R201H mutation can be detected in white blood cells, in approximately 70 per cent of cases. Patients exhibit wide clinical variability with the same molecular defect. This suggests that tissues have different proportions of mutant cells

Hiperostosis cortical generalizada: enfermedad de Van Buchen / Hyperostosis corticales generalisata

Se presenta un caso de enfermedad de Van Bachen (hiperostosis cortical generalizada) y se hace una revisión clínico-radiológica de esta rara enfermedad, comparando los hallazgos del paciente presentado con los casos expuestos por otros autores, incluyendo los del descubridor de la afección. Se realiza un análisis de los distintos diagnósticos diferenciales con otras enfermedades osteoesclerosantes que pueden llevar a confusión