Clinical Overview > Topic
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Department of Biomedical Research, University of Bern, Switzerland
Kuopio Pediatric Research Unit (KuPRu), University of Eastern Finland, Kuopio, Finland
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Department of Nephrology, Bern University Hospital, University of Bern, Switzerland
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Department of Biomedical Research, University of Bern, Switzerland
Graduate School of Cellular and Biomedical Sciences, University of Bern, Switzerland
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Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark
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Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Department of Biomedical Research, University of Bern, Switzerland
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Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark
Department of Clinical Medicine, Aarhus University Hospital, Aarhus N, Denmark
Search for other papers by Claus H Gravholt in
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Summary
Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future.
Learning points
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Non-classic 3βHSD2 is likely underdiagnosed.
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Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis.
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Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections.
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Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.
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Department of Biomedical Informatics, University of Colorado, Aurora, Colorado, USA
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Summary
Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by germline-activating pathogenic variants in the RET proto-oncogene. MEN2A is the most common subtype, with a risk for medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), whereas MEN2B is less common and associated with MTC and PHEO along with mucosal neuromas. Little is known about the specific RET germline heterozygous variant K666N. This variant has been described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. There is one case of MTC and bilateral PHEO. The RET K666N variant is not stratified yet by the American Thyroid Association, and data are limited on pathogenicity; therefore, appropriate screening and treatment of asymptomatic RET K666N carriers are unclear. Here, we report a family with a heterozygous germline RET K666N variant. The proband was identified when she experienced cardiogenic shock and multi-organ failure after an elective hysterectomy and subsequently was found to have PHEO, with genetic testing revealing the RET K666N germline variant. Patient consent was obtained through IRB protocol COMIRB #15-0516.
Learning Points
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The specific RET germline heterozygous variant K666N is rare and described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. Our proband is much younger and has PHEO, MTC, and PHPT.
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The RET K666N germline variant appears to be a low penetrance variant for MEN2.
Search for other papers by Ashwini Maudhoo in
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Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
CEI UAM + CSIC, IMDEA Food Institute, Madrid, Spain
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Search for other papers by Lou A Metherell in
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Summary
Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient.
Learning points
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Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases.
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In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing.
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Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.
Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Summary
X-linked adrenoleukodystrophy (X-ALD) is a rare genetic condition caused by mutations in the ABCD1 gene that result in accumulation of very long chain fatty acids (VLCFAs) in various tissues. This leads to demyelination in the CNS and impaired steroidogenesis in the adrenal cortex and testes. A 57-year-old gentleman was referred for the assessment of bilateral gynaecomastia of 6 months duration. He had skin hyperpigmentation since 4 years of age and spastic paraparesis for the past 15 years. Physical examination findings included generalised hyperpigmentation (including skin, buccal mucosa and palmar creases), blood pressure of 90/60 mmHg, non-tender gynaecomastia and bilateral hypoplastic testes. Lower limb findings were those of a profoundly ataxic gait associated with significant paraparesis and sensory loss. Primary adrenal insufficiency was confirmed and investigations for gynaecomastia revealed normal testosterone with mildly elevated luteinising hormone level and normal prolactin. The combination of primary adrenal insufficiency (likely childhood onset), partial testicular failure (leading to gynaecomastia) and spastic paraparesis suggested X-ALD as a unifying diagnosis. A serum VLCFA panel was consistent with X-ALD. Subsequent genetic testing confirmed the diagnosis. Treatment with replacement doses of corticosteroid resulted in improvement in blood pressure and increased energy levels. We have reported the case of a 57-year-old man with a very late diagnosis of X-ALD manifested by childhood onset of primary adrenal insufficiency followed by paraparesis and primary hypogonadism in adulthood. Thus, X-ALD should be considered as a possibility in a patient with non-autoimmune primary adrenal insufficiency and neurological abnormalities.
Learning points
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Adult patients with X-ALD may be misdiagnosed as having multiple sclerosis or idiopathic spastic paraparesis for many years before the correct diagnosis is identified.
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Screening for X-ALD with a VLCFA panel should be strongly considered in male children with primary adrenal insufficiency and in male adults presenting with non-autoimmune primary adrenal insufficiency.
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Confirmation of a genetic diagnosis of X-ALD can be very useful for a patient's family as genetic testing enables detection of pre-symptomatic female heterozygotes who can then be offered pre-natal testing to avoid transmission of the disease to male offsprings.
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Summary
We present the case of a 30-year-old female who was diagnosed with hereditary phaeochromocytoma secondary to a rare gene mutation in exon 8 of the RET oncogene. This genetic mutation was picked up as part of an extended genetic screen using a method known as next generation sequencing. Detection of this genetic mutation prompted further screening for the manifestation of multiple endocrine neoplasia type 2A (MEN2A). The patient subsequently underwent a thyroidectomy with histology confirming C-cell hyperplasia.
Learning points
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Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma.
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Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma.
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Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.
