A CASE REPORT ON ANDROGEN INSENSITIVITY SYNDROME

Androgen Insensitivity Syndrome is an X linked disorder resulting in normal masculinization of external genitalia due to loss of function mutation in AR gene. Case Report : A 18 year old female presented with C/O not attaining menarche. Patient gives a history of lack of development of pubic and axillary hair. No history of abnormal breast development,cyclical abdominal pain or excessive weight gain. No relevant family history. O/E No palpable swellings in abdomen or bilateral inguinal region. External genitalia appear like a normal female external genitalia. The patient's karyotyping was done and it is of male genotype. The patient is diagnosed as Complete AIS as the phenotype is female and genetically male. The patient is managed by laparoscopic B/L orchidectomy with B/L deep ring closure.

Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas

Purpose. Recently, pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a CHEK2 strong association has been observed. Therefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in PPGLs. Methods. Four patients with CHEK2 mutations were recruited, as previously detected by the whole exome sequencing. Sanger sequencing was used to verify the germline mutations as well as the loss of heterozygosities (LOHs) in their somatic DNAs. Immunohistochemistry was used to analyze the expression of CHEK2 and its downstream target p53 Ser20 (phosphorylated p53). Results. The average age of studied patients was 44.25 ± 11.18 years, at the time diagnosis. One patient had multiple tumors which recurred quickly, while two patients had distant metastasis. None of the patient had any relevant family history. Four germline CHEK2 mutations were identified (c.246_260del; c.715G > A; c.1008+3A > T; and c.1111C > T). All the patients were predicted to have either pathogenic or suspected pathogenic mutations. There was no LOH of CHEK2 gene in somatic DNAs found. Additionally, neither CHEK2 proteins nor its downstream target p53 Ser20 were expressed in the tumor tissues. The inactivation of CHEK2 leads to the decrease in the p53 phosphorylation, which might promote tumorigenesis. Conclusions. For the first time, CHEK2 was identified as a susceptibility gene for PPGLs. However, the penetrance of CHEK2 gene with genotype-phenotype correlation needs to be investigated.

Etiological investigation of genetic cause in autism spectrum disorder

AIMS: The aims of this study were to characterize the etiological investigation of genetic cause in the autism spectrum disorder and to determine the factors related to its identification.METHODS: A retrospective descriptive study, with an analytical component, included children and adolescents with autism spectrum disorder followed in consultation at a level 2 hospital, between November 2017 and October 2019. The following variables were analyzed: age, sex, age at the first consultation, family history, objective examination, cognitive assessment, etiological investigation of genetic cause and etiological diagnosis of genetic cause. Statistical analysis was performed using the SPSS®v23 program (significance level 0.05).RESULTS: We identified 153 children with autism spectrum disorder, of which 48 underwent a genetic cause investigation: 45 performed microarray analysis (15.6% pathogenic); 42 carried out a molecular study of the Fragile X syndrome (one altered); two performed sequencing of the methyl CpG binding protein 2 (MECP2) gene (one altered). The diagnosis of genetic cause was made in 18.8% of the sample. The identification of the etiology of a genetic cause was related to global development delay/ intellectual disability (p = 0.04) and the presence of relevant family history (p = 0.005).CONCLUSIONS: The diagnostic yield of the genetic study was higher in patients with a global development delay /intellectual disability and in patients with relevant family history.

Keratolytic Winter Erythema: a misdiagnosed palmoplantar dermatosis

<p class="abstract">Keratolytic Winter Erythema, also known as ‘Erythrokeratolysis hiemalis’ or ‘Oudtshoorn disease’ is a rare genetic disorder of keratinization of an unknown etiology characterized by cyclical erythema and intermittent skin peeling usually over palms and soles, particularly during winter.It was originally described in South African families of European descent originating from the Oudtshoorn district of Cape Provence, and has been since identified in several other countries. It is an autosomal dominant disorder with variable penetrance. The condition <a name="_Hlk67093214"></a>is often misdiagnosed as Keratolysis exfoliativa, but presence of a relevant family history, winter exacerbation and preceding hyperhidrosis with interdigital involvement differentiate it from the former. We present a case report with clinical histopathological data of an 18-year-old female with attributes of erthrokeratolysis hiemalis. This case is being reported due to its rarity.</p>

Non-syndromic oligodontia in siblings: A spectrum of experience

Non-syndromic oligodontia, the agenesis of six or more teeth, has a prevalence of 0.14–0.25%. Genetic, epigenetic and environmental influences affect expression. Three brothers presented with agenesis of 14, 21 and 23 permanent teeth, respectively. They were medically well, with no relevant family history. Each case presented with caries, microdontia and attritive tooth surface loss. Comprehensive care was delivered in each case by undergraduate dental students. Individualized prevention and stabilization were completed before referral for multidisciplinary long-term planning. Primary dental care practitioners are instrumental in delivering preventive care and stabilizing the dentition in cases of dental anomaly, while sharing care with specialist teams. CPD/Clinical Relevance: An unusual presentation of non-syndromic oligodontia relevant to primary dental care practitioners who are likely to provide the first clinical contact and referral to the wider multidisciplinary team.

Young-onset frontotemporal dementia with FUS pathology

Frontotemporal dementia (FTD) is an uncommon cause of behavioural change in adults under the age of 50. A 44-year-old man presented with progressive neuropsychiatric disturbance characterised by social withdrawal, apathy, loss of empathy, motor stereotypies and hyperorality. Cognitive testing identified severe impairment, including executive dysfunction. MR scan of the brain showed bilateral symmetrical frontal atrophy. There was no relevant family history, and targeted genetic testing for FTD-associated variants in MAPT, GRN and C9orf72 genes proved negative. He became more withdrawn with disinhibited behaviour; his condition progressively worsened and he died 6 years later. The pathological diagnosis was frontotemporal lobar degeneration with fused-in-sarcoma (FUS) pathology, a rare sporadic cause of FTD, accounting for only 5%–10% of cases, its characteristic features including very young onset, motor stereotypies and hyperorality.

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes

Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation. Qualitative methods were used to explore behavioural and psychosocial consequences of disclosure. ICC genes were analysed in genome sequence data from 7203 research participants; a two-stage approach was used to recruit genotype-blind variant carriers and matched controls. Cardiac-focused medical and family history collection and genetic counselling were followed by standard clinical tests, blinded to genotype. Pathogenic ICC variants were identified in 0.61% of individuals; 20 were eligible for the present study. Four variant carriers and seven non-carrier controls participated. One variant carrier had a family history of ICC and was clinically affected; a second was clinically unaffected and had no relevant family history. One variant, in two unrelated participants, was subsequently reclassified as being of uncertain significance. Analysis of qualitative data highlights participant satisfaction with approach, willingness to follow clinical recommendations, but variable outcomes of relatives’ engagement with healthcare services. In conclusion, when offered access to SF, many people choose not to pursue them. For others, disclosure of ICC SF in a specialist setting is valued and of likely clinical utility, and can be expected to identify individuals with, and without a phenotype.

Colitis Cystica Profunda with Gastrointestinal Stromal Tumor: A Case Report

Backgroud: Colitis Cystica Profunda(CCP) is a rare benign medical condition and its exact etiology is still unknown. The clinical symptoms could be atypical and even asymptomatic, and also associated with several diseases. Most CCP patients may be misdiagnosed due to its complexity, and can be recognized after long-term medical treatment or surgical resection, especially in the elder or patients with relevant family history. Case presentation: In this case, a 58-year-old man presented with change in bowel habits for 3 years. Gastroscopy and colonoscopy were performed, and the lesions in stomach were resected. Colonoscopy revealed most lesions were significantly smaller after the resection of stomach neoplasm. Notably, these lesions recurred 3 years later. Conclusion: This case is an important reference for primary physician and pathologist to make correct diagnosis through initial endoscopic and pathological examination.

The Genetics of Pituitary Adenomas

The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called “3 P association” of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.

Delayed-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by a novel mutation in DAX1

In this study, we described a male who presented with delayed-onset adrenal hypoplasia congenita (AHC) and mild hypogonadotropic hypogonadism (HHG) without a relevant family history. A novel mutation in the DAX1 (dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1) gene was shown to cause X-linked AHC and HHG. Genetic analysis revealed a novel nonsense mutation, c.154G > T (p.Glu52Term), in the DAX1 gene. Molecular testing demonstrated that the milder phenotype caused by this mutation was due to expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine at codon 83). This unusual case revealed a potential mechanism for a novel mutation that resulted in an unusual delayed-onset mild clinical phenotype. It expands the spectrum of adrenal hypoplasia congenita and hypogonadotropic hypogonadism.