Diagnosis and Treatment > Investigation > Molecular genetic analysis
You are looking at 31 - 40 of 69 items
Search for other papers by M A Shehab in
Google Scholar
PubMed
Search for other papers by Tahseen Mahmood in
Google Scholar
PubMed
Search for other papers by M A Hasanat in
Google Scholar
PubMed
Search for other papers by Md Fariduddin in
Google Scholar
PubMed
Search for other papers by Nazmul Ahsan in
Google Scholar
PubMed
Search for other papers by Mohammad Shahnoor Hossain in
Google Scholar
PubMed
Search for other papers by Md Shahdat Hossain in
Google Scholar
PubMed
Search for other papers by Sharmin Jahan in
Google Scholar
PubMed
Summary
Congenital adrenal hyperplasia (CAH) due to the three-beta-hydroxysteroid-dehydrogenase (3β-HSD) enzyme deficiency is a rare autosomal recessive disorder presenting with sexual precocity in a phenotypic male. Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy presenting with hypergonadotropic hypogonadism in a male. However, only a handful of cases of mosaic KS have been described in the literature. The co-existence of mosaic KS with CAH due to 3β-HSD enzyme deficiency portrays a unique diagnostic paradox where features of gonadal androgen deficiency are masked by simultaneous adrenal androgen excess. Here, we report a 7-year-old phenotypic male boy who, at birth presented with ambiguous genitalia, probably a microphallus with penoscrotal hypospadias. Later on, he developed accelerated growth with advanced bone age, premature pubarche, phallic enlargement and hyperpigmentation. Biochemically, the patient was proven to have CAH due to 3β-HSD deficiency. However, the co-existence of bilateral cryptorchidism made us to consider the possibility of hypogonadism as well, and it was further explained by concurrent existence of mosaic KS (47,XXY/46,XX). He was started on glucocorticoid and mineralocorticoid replacement and underwent right-sided orchidopexy on a later date. He showed significant clinical and biochemical improvement on subsequent follow-up. However, the declining value of serum testosterone was accompanied by rising level of FSH thereby unmasking hypergonadotropic hypogonadism due to mosaic KS. In future, we are planning to place him on androgen replacement as well.
Learning points:
-
Ambiguous genitalia with subsequent development of sexual precocity in a phenotypic male points towards some unusual varieties of CAH.
-
High level of serum testosterone, adrenal androgen, plasma ACTH and low basal cortisol are proof of CAH, whereas elevated level of 17-OH pregnenolone is biochemical marker of 3β-HSD enzyme deficiency.
-
Final diagnosis can be obtained with sequencing of HSD3B2 gene showing various mutations.
-
Presence of bilateral cryptorchidism in such a patient may be due to underlying hypogonadism.
-
Karyotyping in such patient may rarely show mosaic KS (47,XXY/46,XX) and there might be unmasking of hypergonadotropic hypogonadism resulting from adrenal androgen suppression from glucocorticoid treatment.
Specialist Medicine, Manchester University Foundation Trust, Manchester, UK
Search for other papers by Ellena Cotton in
Google Scholar
PubMed
Search for other papers by David Ray in
Google Scholar
PubMed
Summary
A young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when she became amenorrhoic. The mutation was identified as a result of family screening following the early death of the patient’s daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigations were initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raised prolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed. Dicer is an RNase enzyme, which is essential for processing small non-coding RNAs. These molecules play pleiotropic roles in regulating gene expression, by targeting mRNA sequences for degradation. DICER1 plays different roles depending on cell context, but is thought to be a functional tumour suppressor gene. Accordingly, germline mutation in one DICER1 allele is insufficient for oncogenesis, and a second hit on the other allele is required, as a result of postnatal somatic mutation. Loss of DICER1 is linked to multiple tumours, with prominent endocrine representation. Multinodular goitre is frequent, with increased risk of differentiated thyroid cancer. Rare, developmental pituitary tumours are reported, including pituitary blastoma, but not reports of functional pituitary adenomas. As DICER1 mutations are rare, case reports are the only means to identify new manifestations and to inform appropriate screening protocols.
Learning points:
-
DICER1 mutations lead to endocrine tumours.
-
DICER1 is required for small non-coding RNA expression.
-
DICER1 carriage and microprolactinoma are both rare, but here are reported in the same individual, suggesting association.
-
Endocrine follow-up of patients carrying DICER1 mutations should consider pituitary disease.
Department of Endocrinology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
Search for other papers by Benjamin Kwan in
Google Scholar
PubMed
Department of Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
Search for other papers by Bernard Champion in
Google Scholar
PubMed
Department of Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia
Search for other papers by Steven Boyages in
Google Scholar
PubMed
The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
Search for other papers by Craig F Munns in
Google Scholar
PubMed
Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
Search for other papers by Roderick Clifton-Bligh in
Google Scholar
PubMed
Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
Search for other papers by Catherine Luxford in
Google Scholar
PubMed
Department of Endocrinology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
Search for other papers by Bronwyn Crawford in
Google Scholar
PubMed
Summary
Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.
Learning points:
-
ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.
-
In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.
-
CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.
-
Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.
Search for other papers by Haruhiro Sato in
Google Scholar
PubMed
Department of Pediatrics, Keio Hachioji Clinic, Hchioji, Tokyo, Japan
Search for other papers by Yuichiro Tomita in
Google Scholar
PubMed
Summary
Resistance to thyroid hormone (RTH), which is primarily caused by mutations in the thyroid hormone (TH) receptor beta (THRB) gene, is dominantly inherited syndrome of variable tissue hyposensitivity to TH. We herein describe a case involving a 22-year-old Japanese man with RTH and atrial fibrillation (AF) complaining of palpitation and general fatigue. Electrocardiography results revealed AF. He exhibited elevated TH levels and an inappropriately normal level of thyroid-stimulating hormone (TSH). Despite being negative for anti-TSH receptor antibody, thyroid-stimulating antibody and anti-thyroperoxidase antibody, the patient was positive for anti-thyroglobulin (Tg) antibody. Genetic analysis of the THRB gene identified a missense mutation, F269L, leading to the diagnosis of RTH. Normal sinus rhythm was achieved after 1 week of oral bisoprolol fumarate (5 mg/day) administration. After 3 years on bisoprolol fumarate, the patient had been doing well with normal sinus rhythm, syndrome of inappropriate secretion of TSH (SITSH) and positive titer of anti-Tg antibody.
Learning points:
-
Atrial fibrillation can occur in patients with RTH.
-
Only a few cases have been reported on the coexistence of RTH and atrial fibrillation.
-
No consensus exists regarding the management of atrial fibrillation in patients with RTH.
-
Administration of bisoprolol fumarate, a beta-blocker, can ameliorate atrial fibrillation in RTH.
Eastern Health Clinical School, Monash University, Victoria, Australia
Search for other papers by Ming Li Yee in
Google Scholar
PubMed
Search for other papers by Rosemary Wong in
Google Scholar
PubMed
Medical Imaging, Eastern Health, Box Hill, Victoria, Australia
Search for other papers by Mineesh Datta in
Google Scholar
PubMed
Department of Medicine and Radiology, University of Melbourne, Victoria, Australia
Search for other papers by Timothy Nicholas Fazio in
Google Scholar
PubMed
Search for other papers by Mina Mohammad Ebrahim in
Google Scholar
PubMed
Search for other papers by Elissa Claire Mcnamara in
Google Scholar
PubMed
Search for other papers by Gerard De Jong in
Google Scholar
PubMed
Eastern Health Clinical School, Monash University, Victoria, Australia
Department of Medicine, Eastern Health, Box Hill, Victoria, Australia
Search for other papers by Christopher Gilfillan in
Google Scholar
PubMed
Summary
Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism. Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the most common endocrinopathy, and recognition of these patients is important due to its impact on management and screening of family members. In particular, glycemic management differs in these patients: the use of metformin is avoided because of the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation of hyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafness and a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder.
Learning points:
-
The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration of a mitochondrial disorder.
-
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>G in 80% of cases.
-
Metformin should be avoided due to the risk of lactic acidosis.
-
There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared to type 2 diabetes.
-
Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for future complications.
-
Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in cases of significant weight loss, has been reported in MELAS patients.
Search for other papers by Daniela Regazzo in
Google Scholar
PubMed
Search for other papers by Marina Paola Gardiman in
Google Scholar
PubMed
Search for other papers by Marily Theodoropoulou in
Google Scholar
PubMed
Search for other papers by Carla Scaroni in
Google Scholar
PubMed
Search for other papers by Gianluca Occhi in
Google Scholar
PubMed
Search for other papers by Filippo Ceccato in
Google Scholar
PubMed
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hereditary cutaneous condition, characterized by multiple hamartomas. In rare cases, pituitary neuroendocrine tumors (PitNETs) have been described in patients with TSC, but the causal relationship between these two diseases is still under debate. TSC is mostly caused by mutations of two tumor suppressor genes, encoding for hamartin (TSC1) and tuberin (TSC2), controlling cell growth and proliferation. Here, we present the case of a 62-year-old Caucasian woman with TSC and a silent gonadotroph PitNET with suprasellar extension, treated with transsphenoidal endoscopic neurosurgery with complete resection. Therapeutic approaches based on mTOR signaling (i.e. everolimus) have been successfully used in patients with TSC and tested in non-functioning PitNET cellular models with promising results. Here, we observed a reduction of cell viability after an in vitro treatment of PitNET’s derived primary cells with everolimus. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in TSC2: the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an in vitro analysis of patient’s lymphocyte-derived RNA. Further analyses are therefore needed to provide insights on the possible mechanisms involving the hamartin-tuberin complex in the pathogenesis of pituitary adenomas. However, our data further support previous observations of an antiproliferative effect of everolimus on PitNET.
Learning points:
-
Pituitary neuroendocrine tumors (PitNET) in patients with tuberous sclerosis complex (TSC) are rare: only few cases have been reported in literature.
-
Therapeutic approach related to mTOR signaling, such as everolimus, may be used in some patients with PitNETs as well as those with TSC.
-
We reported a woman with both non-secreting PitNET and TSC; PitNET was surgically removed and classified as a silent gonadotroph tumor.
-
Everolimus treatment in PitNET’s-derived primary cells revealed a significant decrease in cell viability.
-
Considering our case and available evidence, it is still unclear whether a PitNET is a part of TSC or just a coincidental tumor.
Search for other papers by Yang Timothy Du in
Google Scholar
PubMed
Search for other papers by Angus Rutter in
Google Scholar
PubMed
Search for other papers by Jui T Ho in
Google Scholar
PubMed
Summary
A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways.
Learning points:
-
The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.
-
Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.
-
Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.
National University of Ireland, Galway, Ireland
Search for other papers by Michelle Maher in
Google Scholar
PubMed
Search for other papers by Federico Roncaroli in
Google Scholar
PubMed
Search for other papers by Nigel Mendoza in
Google Scholar
PubMed
Search for other papers by Karim Meeran in
Google Scholar
PubMed
Search for other papers by Natalie Canham in
Google Scholar
PubMed
Search for other papers by Monika Kosicka-Slawinska in
Google Scholar
PubMed
Search for other papers by Birgitta Bernhard in
Google Scholar
PubMed
Search for other papers by David Collier in
Google Scholar
PubMed
Search for other papers by Juliana Drummond in
Google Scholar
PubMed
Search for other papers by Kassiani Skordilis in
Google Scholar
PubMed
Search for other papers by Nicola Tufton in
Google Scholar
PubMed
Search for other papers by Anastasia Gontsarova in
Google Scholar
PubMed
Search for other papers by Niamh Martin in
Google Scholar
PubMed
Search for other papers by Márta Korbonits in
Google Scholar
PubMed
Search for other papers by Florian Wernig in
Google Scholar
PubMed
Summary
Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient’s SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient’s father’s paraganglioma.
Learning points:
-
Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease.
-
SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.
-
Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.
-
Immunohistochemistry may not always predict the presence of SDHx mutations.
Autonomous University of Barcelona, Barcelona, Spain
Search for other papers by E Mogas in
Google Scholar
PubMed
Autonomous University of Barcelona, Barcelona, Spain
Search for other papers by A Campos-Martorell in
Google Scholar
PubMed
Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Search for other papers by M Clemente in
Google Scholar
PubMed
Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, Cruces University Hospital, Barakaldo, Spain
Search for other papers by L Castaño in
Google Scholar
PubMed
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Department of Pediatrics, Children’s University Hospital Vall Hebron, Barcelona, Spain
Search for other papers by A Moreno-Galdó in
Google Scholar
PubMed
Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Search for other papers by D Yeste in
Google Scholar
PubMed
Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Search for other papers by A Carrascosa in
Google Scholar
PubMed
Summary
Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results.
Learning points:
-
Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.
-
Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.
-
Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.
-
Treatment has been well tolerated and no side effects have been detected.
Search for other papers by Maria P Yavropoulou in
Google Scholar
PubMed
Search for other papers by Christos Poulios in
Google Scholar
PubMed
Search for other papers by Christoforos Foroulis in
Google Scholar
PubMed
Search for other papers by Symeon Tournis in
Google Scholar
PubMed
Search for other papers by Prodromos Hytiroglou in
Google Scholar
PubMed
Search for other papers by Kalliopi Kotsa in
Google Scholar
PubMed
Search for other papers by Isaak Kessisoglou in
Google Scholar
PubMed
Search for other papers by Pantelis Zebekakis in
Google Scholar
PubMed
Summary
Tumor-induced osteomalacia (TIO) is a rare form of hypophosphatemia usually caused by phosphaturic mesenchymal tumors (PMTs); the biologic behavior of PMTs is under investigation. Herein we present a case of TIO with a protracted course over 12 years leading to a fatal outcome. A 39-year-old man presented with weakness in 2004 and was found to have decreased serum phosphorus, phosphaturia and low levels of 1,25-dihydroxyvitamin D3. Four years later he developed a painful left calf mass. The lesion was resected, but recurred causing extreme pain and dysfunction. Radiological examination showed a large cluster of soft tissue tumors affecting all the muscle compartments of the calf and a smaller lesion inside the metaphysis of the tibia. Above-knee amputation was performed. Histological examination of all lesions showed a cellular spindle cell neoplasm with variously sized vessels, wide vessel-like spaces and scattered deposits of calcified extracellular material. The tumor infiltrated skeletal muscles, subcutaneous fat and the proximal end of the fibula. The tibial lesion had identical histology. Three years after the amputation the patient presented with cough and dyspnea. Radiological examination, followed by an open biopsy, showed that there were multiple metastatic nodules of PMTs in both lungs. Shortly after the diagnosis the patient died. This case illustrates that even benign cases of PMTs may lead to a fatal outcome and the classification of PMTs into benign and malignant should be reassessed in order to correspond to its biological behavior.
Learning points:
-
PMTs, aside from having locally aggressive behavior, may metastasize and cause death
-
PMTs may behave aggressively despite ‘benign’ histological findings
-
Accurate diagnosis of tumor-induced osteomalacia and patient management require a multidisciplinary approach
