Diagnosis and Treatment > Investigation > Chromosomal analysis
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Summary
Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of luteinizing hormone (LH) receptor in patients with PA has been reported; however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a 2-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered.
Learning points:
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The pathogenesis of primary aldosteronism is still unclear.
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Expression of luteinizing hormone receptor has been reported in aldosterone-producing adenoma.
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Serum luteinizing hormone, which is increased in patients with Klinefelter’s syndrome, might contribute to the development of primary aldosteronism.
Search for other papers by Yotsapon Thewjitcharoen in
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Search for other papers by Thep Himathongkam in
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Summary
Primary amenorrhea could be caused by disorders of four parts: disorders of the outflow tract, disorders of the ovary, disorders of the anterior pituitary, and disorders of hypothalamus. Delay in diagnosis and hormone substitution therapy causes secondary osteoporosis. Herein, we report a case of a 23-year-old phenotypical female who presented with primary amenorrhea from 46, XX gonadal dysgenesis but had been misdiagnosed as Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis. The coexistence of gonadal dysgenesis and MRKH was suspected after laboratory and imaging investigations. However, the vanishing uterus reappeared after 18 months of hormone replacement therapy. Therefore, hormone profiles and karyotype should be thoroughly investigated to distinguish MRKH syndrome from other disorders of sex development (DSD). Double diagnosis of DSD is extremely rare and periodic evaluation should be reassessed. This case highlights the presence of estrogen deficiency state, the uterus may remain invisible until adequate exposure to exogenous estrogen.
Learning points:
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An early diagnosis of disorders of sex development (DSD) is extremely important in order to promptly begin treatment, provide emotional support to the patient and reduce the risks of associated complications.
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Hormone profiles and karyotype should be investigated in all cases of the presumptive diagnosis of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis.
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The association between 46, XX gonadal dysgenesis and Mullerian agenesis has been occasionally reported as a co-incidental event; however, reassessment of the presence of uterus should be done again after administration of exogenous estrogen replacement for at least 6–12 months.
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A multidisciplinary approach is necessary for patients presenting with DSD to ensure appropriate treatments and follow-up across the lifespan of individuals with DSD.
Memorial University Medical Center, Savannah, Georgia, USA
Search for other papers by Himangshu S Bose in
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Pediatric Endocrinology and Diabetes Center, Kalispell Regional Medical Center, Kalispell, Montana, USA
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Search for other papers by Brendan Marshall in
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Laboratory of Pathology, Memorial University Medical Center, Savannah, Georgia, USA
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Search for other papers by Elizabeth W Perry in
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Summary
Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells.
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Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells;
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Testicular mitochondrial size was small with little SCC expression within the mitochondria;
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Absence of pregnenolone is associated with organelle stress.
Search for other papers by Priya Vaidyanathan in
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Search for other papers by Paul Kaplowitz in
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Summary
Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene.
Learning points:
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Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization.
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The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS.
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Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.
Search for other papers by M A Shehab in
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Search for other papers by Tahseen Mahmood in
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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:
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Ambiguous genitalia with subsequent development of sexual precocity in a phenotypic male points towards some unusual varieties of CAH.
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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.
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Final diagnosis can be obtained with sequencing of HSD3B2 gene showing various mutations.
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Presence of bilateral cryptorchidism in such a patient may be due to underlying hypogonadism.
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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.
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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:
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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.
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Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.
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Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.
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Summary
Deletion of chromosome 2q37 results in a rare congenital syndrome known as brachydactyly mental retardation (BDMR) syndrome; a syndrome which has phenotypes similar to Albright hereditary osteodystrophy (AHO) syndrome. In this report, we describe a patient with AHO due to microdeletion in long arm of chromosome 2 [del(2)(q37.3)] who had growth hormone (GH) deficiency, which is a unique feature among reported BDMR cases. This case was presented with shortening of the fourth and fifth metacarpals which along with AHO phenotype, brings pseudopseudohypoparathyroidism (PPHP) and pseudohypoparathyroidism type Ia (PHP-Ia) to mind; however, a genetic study revealed del(2)(q37.3). We recommend clinicians to take BDMR in consideration when they are faced with the features of AHO; although this syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia. Moreover, we recommend evaluation of IGF 1 level and GH stimulation test in patients with BDMR whose height is below the 3rd percentile.
Learning points:
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Clinicians must have brachydactyly mental retardation (BDMR) syndrome in consideration when they are faced with the features of Albright hereditary osteodystrophy.
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Although BDMR syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia.
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Evaluation of IGF1 level in patients diagnosed with BDMR whose height is below the 3rd percentile is important.
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Summary
Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism in combination with a defect in sense of smell, due to abnormal migration of gonadotropin-releasing hormone-producing neurons. We report a case of a 17-year-old Tunisian male who presented with eunuchoid body proportions, absence of facial, axillary and pubic hair, micropenis and surgically corrected cryptorchidism. Associated findings included anosmia. Karyotype was 46XY and hormonal measurement hypogonadotropic hypogonadism. MRI of the brain showed bilateral agenesis of the olfactory bulbs and 3.5 mm pituitary microadenoma. Hormonal assays showed no evidence of pituitary hypersecretion.
Learning points:
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The main clinical characteristics of KS include hypogonadotropic hypogonadism and anosmia or hyposmia.
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MRI, as a non-irradiating technique, should be the first radiological step for investigating the pituitary gland as well as abnormalities of the ethmoid, olfactory bulbs and tracts in KS.
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KS may include anterior pituitary hypoplasia or an empty sella syndrome. The originality of our case is that a microadenoma also may be encountered in KS. Hormonal assessment indicated the microadenoma was non-functioning. This emphasizes the importance of visualizing the pituitary region in KS patients to assess for hypoplastic pituitary malformations or adenomas.
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Summary
Growth anomaly is a prominent feature in Wolf-Hirschhorn syndrome (WHS), a rare congenital disorder caused by variable deletion of chromosome 4p. While growth charts have been developed for WHS patients 0–4 years of age and growth data available for Japanese WHS patients 0–17 years, information on pubertal growth and final height among WHS children remain lacking. Growth hormone (GH) therapy has been reported in two GH-sufficient children with WHS, allowing for pre-puberty catch up growth; however, pubertal growth and final height information was also unavailable. We describe the complete growth journey of a GH-sufficient girl with WHS from birth until final height (FH), in relation to her mid parental height (MPH) and target range (TR). Her growth trajectory and pubertal changes during childhood, when she was treated with growth hormone (GH) from 3 years 8 months old till 6 months post-menarche at age 11 years was fully detailed.
Learning points:
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Pubertal growth characteristics and FH information in WHS is lacking.
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While pre-pubertal growth may be improved by GH, GH therapy may not translate to improvement in FH in WHS patients.
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Longitudinal growth, puberty and FH data of more WHS patients may improve the understanding of growth in its various phases (infancy/childhood/puberty).
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Summary
In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.
Learning points:
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CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.
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CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.
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Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.
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Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.
