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Open access

Kohei Saitoh, Takako Yonemoto, Takeshi Usui, Kazuhiro Takekoshi, Makoto Suzuki, Yoshiharu Nakashima, Koji Yoshimura, Rieko Kosugi, Tatsuo Ogawa and Tatsuhide Inoue

Summary

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumours with a heterogeneous genetic background. Up to 40% of apparently sporadic PCC/PGL cases carry 1 of the 12 gene germline mutations conferring genetic susceptibility to PCC/PGL. Although the precise mechanisms are unclear, TMEM127 is one of the rare responsible genes for PCC/PGL. Here we report the case of a patient with familial PCC having a novel TMEM127 variant (c.119C > T, p.S40F). In silico prediction analysis to evaluate the functional significance of this variant suggested that it is a disease-causing variant. A PCC on the left side was considered to be the dominant lesion, and unilateral adrenalectomy was performed. The histopathologic findings were consistent with benign PCC. A loss of heterogeneity of the TMEM127 variant was detected in the surgically removed tumour.

Learning points:

  • c.119C > T (p.S40F) is a novel TMEM127 variant that can cause pheochromocytoma.

  • The tumour showed loss of heterozygosity of this TMEM127 variant.

  • The clinical phenotype of this mutation is putative bilateral pheochromocytoma in the 4th decade.

  • Unilateral adrenalectomy may be performed as the initial surgery in such cases.

Open access

Teresa Rego, Fernando Fonseca, Stéphanie Espiard, Karine Perlemoine, Jérôme Bertherat and Ana Agapito

Summary

PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20–90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient’s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.

Learning points:

  • PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.

  • The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.

  • Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene.

  • The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.

  • As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.

Open access

Rowena Speak, Jackie Cook, Barney Harrison and John Newell-Price

Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.

Learning points:

  • C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.

  • C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.

  • There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.

Open access

Asma Deeb, Hana Al Suwaidi, Salima Attia and Ahlam Al Ameri

Summary

Combined17α-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Hypertension and hypokalemia are essential presenting features. We report an Arab family with four affected XX siblings. The eldest presented with abdominal pain and was diagnosed with a retroperitoneal malignant mixed germ cell tumour. She was hypertensive and hypogonadal. One sibling presented with headache due to hypertension while the other two siblings were diagnosed with hypertension on a routine school check. A homozygous R96Q missense mutation in P450c17 was detected in the index case who had primary amenorrhea and lack of secondary sexual characters at 17 years. The middle two siblings were identical twins and had no secondary sexual characters at the age of 14. All siblings had hypokalemia, very low level of adrenal androgens, high ACTH and high levels of aldosterone substrates. Treatment was commenced with steroid replacement and puberty induction with estradiol. The index case had surgical tumor resection and chemotherapy. All siblings required antihypertensive treatment and the oldest remained on two antihypertensive medications 12 years after diagnosis. Her breast development remained poor despite adequate hormonal replacement. Combined 17α-hydroxylase/17,20-lyase deficiency is a rare condition but might be underdiagnosed. It should be considered in young patients presenting with hypertension, particularly if there is a family history of consanguinity and with more than one affected sibling. Antihypertensive medication might continue to be required despite adequate steroid replacement. Breast development may remain poor in mutations causing complete form of the disease.

Learning points

  • Endocrine hypertension due to rarer forms of CAH should be considered in children and adolescents, particularly if more than one sibling is affected and in the presence of consanguinity.

  • 17α-hydroxylase/17,20-lyase deficiency is a rare form of CAH but might be underdiagnosed.

  • Blood pressure measurement should be carried out in all females presenting with hypogonadism.

  • Anti-hypertensive medications might be required despite adequate steroid replacement.

  • Initial presenting features might vary within affected members of the same family.

  • Adverse breast development might be seen in the complete enzyme deficiency forms of the disease.