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Open access

Alejandro García-Castaño, Leire Madariaga, Sharona Azriel, Gustavo Pérez de Nanclares, Idoia Martínez de LaPiscina, Rosa Martínez, Inés Urrutia, Aníbal Aguayo, Sonia Gaztambide and Luis Castaño

Summary

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.

Learning points:

  • Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.

  • Large deletions or duplications in the CASR gene can be detected by the MLPA technique.

  • Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

Open access

Durgesh Prasad Chaudhary, Tshristi Rijal, Kunal Kishor Jha and Harpreet Saluja

Summary

Combined pituitary hormonal deficiency (CPHD) is a rare disease that results from mutations in genes coding for transcription factors that regulate the differentiation of pituitary cells. PROP1 gene mutations are one of the etiological diagnoses of congenital panhypopituitarism, however symptoms vary depending on phenotypic expression. We present a case of psychosis in a 36-year-old female with congenital panhypopituitarism who presented with paranoia, flat affect and ideas of reference without a delirious mental state, which resolved with hormone replacement and antipsychotics. Further evaluation revealed that she had a homozygous mutation of PROP1 gene. In summary, compliance with hormonal therapy for patients with hypopituitarism appears to be effective for the prevention and treatment of acute psychosis symptoms.

Learning points:

  • Patients with PROP1 gene mutation may present with psychosis with no impairment in orientation and memory.

  • There is currently inadequate literature on this topic, and further study on the possible mechanisms of psychosis as a result of endocrine disturbance is required.

  • Compliance with hormonal therapy for patients with hypopituitarism appears to be effective for prevention and treatment of acute psychosis symptoms.

Open access

Anil Piya, Jasmeet Kaur, Alan M Rice and Himangshu S Bose

Summary

Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon–intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo.

Learning points:

  • STAR exon 1 deletion caused lipoid CAH.

  • Exon 1 substitution does not affect biochemical activity.

  • StAR promoter is responsible for gonadal development.

Open access

Etienne Larger, Nicolai J Wewer Albrechtsen, Lars H Hansen, Richard W Gelling, Jacqueline Capeau, Carolyn F Deacon, Ole D Madsen, Fumiatsu Yakushiji, Pierre De Meyts, Jens J Holst and Erica Nishimura

Summary

Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.

Learning points:

  • Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.

  • Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.

  • A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

Open access

Lauren J Baker, Anthony J Gill, Charles Chan, Betty P C Lin and Bronwyn A Crawford

Summary

In 2006, a 58-year-old woman presented with thyrotoxicosis. She had undergone left hemithyroidectomy 14 years before for a benign follicular adenoma. Ultrasound imaging demonstrated bilateral cervical lymphadenopathy with enhanced tracer uptake in the left lateral neck on a Technetium-99m uptake scan. Fine-needle aspiration biopsy of a left lateral neck node was insufficient for a cytological diagnosis; however, thyroglobulin (Tg) washings were strongly positive. The clinical suspicion was of functionally active metastatic thyroid cancer in cervical lymph nodes. A completion thyroidectomy and bilateral cervical lymph node dissection were performed. Histology demonstrated benign multinodularity in the right hemithyroid, with bilateral reactive lymphadenopathy and 24 benign hyperplastic thyroid nodules in the left lateral neck that were classified as parasitic thyroid nodules. As there had been a clinical suspicion of thyroid cancer, and the hyperplastic/parasitic thyroid tissue in the neck was extensive, the patient was given ablative radioactive iodine (3.7 GBq). After 2 years, a diagnostic radioactive iodine scan was clear and the serum Tg was undetectable. The patient has now been followed for 7 years with no evidence of recurrence. Archived tissue from a left lateral neck thyroid nodule has recently been analysed for BRAF V600E mutation, which was negative.

Learning points

  • Thyrotoxicosis due to functional thyroid tissue in the lateral neck is very rare and may be due to metastatic thyroid cancer or benign parasitic thyroid tissue.

  • Parasitic thyroid nodules should be considered as a differential diagnosis of lateral neck thyroid deposits, particularly where there is a history of prior thyroid surgery.

  • Parasitic thyroid nodules may occur as a result of traumatic rupture or implantation from a follicular adenoma at the time of surgery.

  • The use of ablative radioactive iodine may be appropriate, as resection of all parasitic thyroid tissue can prove difficult.

  • BRAF mutational analysis of parasitic thyroid tissue may provide extra reassurance in the exclusion of papillary thyroid carcinoma.