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Open access

Catherine D Zhang, Pavel N Pichurin, Aleh Bobr, Melanie L Lyden, William F Young Jr and Irina Bancos

Summary

Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant.

Learning points:

  • PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.
  • The diagnosis of PPNAD should prompt screening for CNC.
  • CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.
  • Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.
Open access

N Chelaghma, S O Oyibo and J Rajkanna

Summary

Hypogonadotrophic hypogonadism is due to impaired or reduced gonadotrophin secretion from the pituitary gland. In the absence of any anatomical or functional lesions of the pituitary or hypothalamic gland, the hypogonadotrophic hypogonadism is referred to as idiopathic hypogonadotrophic hypogonadism (IHH). We present a case of a young lady born to consanguineous parents who was found to have IHH due to a rare gene mutation.

Learning points:

  • The genetic basis of a majority of cases of IHH remains unknown.
  • IHH can have different clinical endocrine manifestations.
  • Patients can present late to the healthcare service because of unawareness and stigmata associated with the clinical features.
  • Family members of affected individuals can be affected to varying degrees.
Open access

C E Stiles, R Thuraisingham, D Bockenhauer, L Platts, A V Kumar and M Korbonits

Summary

29-year-old female presenting with an 8-year history of unexplained hypomagnesaemia, which was severe enough to warrant intermittent inpatient admission for intravenous magnesium. Urinary magnesium was inappropriately normal in the context of hypomagnesaemia indicating magnesium wasting. Ultrasound imaging demonstrated unilateral renal cysts and computed tomography of kidneys, ureters and bladder showed a bicornuate uterus. Referral to genetic services and subsequent testing revealed a de novo HNF1B deletion.

Learning points:

  • HNF1B loss-of-function mutations are one of the most common monogenic causes of congenital anomalies of the kidney and urinary tract.
  • Those with HNF1B mutations may have some of a constellation of features (renal and hepatic cysts, deranged liver function tests, maturity onset diabetes of the young type 5 (MODY5), bicornuate uterus, hyperparathyroidism, hyperuricaemic gout, but presenting features are highly heterogeneous amongst patients and no genotype/phenotype correlation exists.
  • HNF1B mutations are inherited in an autosomal dominant pattern but up to 50% of cases are de novo.
  • HNF1B mutations can be part of the Chr17q12 deletion syndrome, a contiguous gene deletion syndrome.
  • Inorganic oral magnesium replacements are generally poorly tolerated with side effects of diarrhoea. Organic magnesium compounds, such as magnesium aspartate, are better absorbed oral replacement therapies.
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.

Open access

R Casey, S Prendeville, C Joyce and D O'Halloran

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

  • Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma.
  • Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma.
  • Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.

Open access

S A S Aftab, N Reddy, N L Owen, R Pollitt, A Harte, P G McTernan, G Tripathi and T M Barber

Summary

A 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI.

Learning points

  • OI is a rare but important genetic metabolic bone and connective tissue disorder that manifests a diverse clinical phenotype that includes recurrent low-impact fractures.
  • Most mutations that underlie OI occur within exon 50 of the COL1A1 gene (coding for protein constituents of type 1 pro-collagen).
  • The diagnosis of OI is easily missed in its mild form. Early diagnosis is important, and there is a need for improved awareness of OI among health care professionals.
  • OI is a diagnosis of exclusion, although the key diagnostic criterion is through genetic testing for mutations within the COL1A1 gene.
  • Effective management of OI should be instituted through a multidisciplinary team approach that includes a bone specialist (usually an endocrinologist or rheumatologist), a geneticist, an audiometrist and a genetic counsellor. Physiotherapy and orthopaedic surgery may also be required.