Dysgerminoma Probably Due to a Novel SOHLH1-pathogenic Variant Causing Familial Ovarian Dysgenesis.

Pathogenic variants of the SOHLH1 gene are responsible for an autosomal recessive form of ovarian dysgenesis; this gene encodes a transcription factor expressed early in spermatogonia and oocytes and contributes to folliculogenesis. Previously, four affected women from two unrelated families reported homozygous variants in the SOHLH1 gene, but none had a history of gonadal malignancy or a histologic description. We present two sisters and their paternal great-aunt with a history of primary amenorrhea, pubertal delay, and hypergonadotrophism who came from an inbred Mexican family. The proband was the younger sister who was referred for bilateral dysgerminoma. She had a normal blood karyotype, and whole-exome sequencing analysis revealed a novel homozygous missense variant, c.275C>T, in SOHLH1; several family members were also analyzed. In addition to pure dysgerminoma, histopathological analysis revealed an ovarian cortex with fibrosis and almost total absence of follicles. This work confirms the inheritance of ovarian dysgenesis 5, supports the occurrence of cell loss in mouse models, and suggests that affected women should undergo periodic imaging surveillance due to the likely risk of tumor development.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.

Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

Setleis syndrome in Mexican-Nahua sibs due to a homozygous TWIST2 frameshift mutation and partial expression in heterozygotes: review of the focal facial dermal dysplasias and subtype reclassification.

BACKGROUND: The focal facial dermal dysplasias (FFDDs) are a group of inherited disorders of facial development, characterised by bitemporal or preauricular scar-like defects, the former resembling 'forceps marks'. Recently, different homozygous TWIST2 nonsense mutations were reported in unrelated Setleis syndrome (FFDD Type III) patients from consanguineous families, consistent with autosomal recessive inheritance. Mexican-Nahua sibs with facial and ophthalmologic features of FFDD type III were evaluated. METHODS: Genomic DNAs were isolated for sequencing of the TWIST2 gene. The clinical features and inheritance of all previously reported FFDD patients were reviewed. RESULTS: The affected sibs were homozygous for a novel TWIST2 frameshift mutation, c.168delC (p.S57AfsX45). Notably, both parents and two heterozygous sibs had distichiasis and partial absence of lower eyelashes. The FFDD subtypes were reclassified: the 'Brauer-Setleis' phenotype (autosomal dominant with variable expressivity) as FFDD type II; and patients with preauricular lesions as a new subtype, FFDD type IV. CONCLUSIONS: FFDD type III heterozygotes with TWIST2 mutations may have syndromic manifestations. Review of previous FFDD patients resulted in reclassification of the subtypes.

Primeros casos de monosomía 1p36 en México: diagnóstico a considerar en pacientes con retraso mental y dismorfias / First two Mexican cases of monosomy 1p36: possible diagnosis in patients with mental retardation and dysmorphism

Se calcula que la deleción distal del brazo corto del cromosoma1 ocurre en 1 de cada 5000 recién nacidos vivos y condiciona, aproximadamente, el 1,2 por ciento de los casos de retraso mental sin causa aparente. Esta alteración habitualmente no se puede detectar en el cariotipo convencional, por lo que se requieren técnicas de citogenética molecular para evidenciarla. Además de las manifestaciones neurológicas puede ocasionar malformaciones en órganos internos, como cardiopatía congénita, y un fenotipo facial característico. En este informe se describen los hallazgos clínicos y citogenéticos de los primeros dos casos diagnosticados en México, confirmados mediante la técnica de hibridación in situ con fluorescencia, que se comparan con los descritos en la bibliografía. Además, se discute el probable subdiagnóstico de esta entidad, la importancia de su difusión y los datos clínicos útiles para la sospecha diagnóstica.

It is calculated that distal deletion of the short arm of chromosome 1 occurs in one out of every 5000 live births and causes approximately 1.2% of cases of mental retardation of unknown origin. This alteration usually cannot be detected in the standard karyotype, requiring molecular cytogenetic techniques for the diagnosis. In addition to the neurological manifestations, itmay cause internal organs malformations, such as congenitalheart disease, and a characteristic facial phenotype. This report describes the clinical and cytogenetic findings from the first two cases diagnosed in Mexico, confirmed by fluorescence in situ hybridization test, and compares them to those described in the literature. The probable subdiagnosis of this entity, theimportance of improves its recognition and the useful data for the clinical suspicion are also discussed.