Bilateral testicular masses and adrenal insufficiency: is congenital adrenal hyperplasia the only possible diagnosis? First two cases of TARTS described in Addison-only X-linked adrenoleukodystrophy and a brief review of literature.

BACKGROUND: Testicular adrenal rest tumors (TARTs) are benign masses deemed to originate from pluripotent testicular steroidogenic cells that grow under chronic ACTH stimulation. These lesions, occasionally misdiagnosed as Leydig cell tumors (LCTs), are typically described in patients with congenital adrenal hyperplasia (CAH). X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of beta-oxidation with accumulation of very long chain fatty acids (VLCFAs) in various tissues, and a rare cause of primary adrenal insufficiency (PAI). TARTs have never been associated with X-ALD. CASE 1 DESCRIPTION: A 19-year old male, who had previously undergone bilateral enucleation of presumed LCTs, was referred to our unit. Follow-up scans showed persistent bilateral lesions compatible with TARTs. Biochemical exams revealed PAI but excluded CAH. A serum VLCFAs panel was consistent with X-ALD, with gene testing confirming the diagnosis. Histological revision of the previously resected testicular lesions was compatible with TARTs. Start of glucocorticoid replacement therapy was associated with a reduction of testicular masses. CASE 2 DESCRIPTION: A 26-year old X-ALD male was diagnosed with bilateral testicular lesions compatible with TARTs. These lesions increased after ACTH elevation following switch to modified-release hydrocortisone. Clinical and sonographic findings allowed for a "watchful-waiting" approach, avoiding unnecessary surgery. CONCLUSION: These are the first cases reported of TARTs in patients with X-ALD-associated PAI. Testicular lesions in patients with an early onset of ACTH elevation, regardless of the cause, should always be thoughtfully investigated, as they may reveal themselves as TARTs. We suggest that all patients affected from chronic ACTH elevation of a young age of onset should undergo testicular ultrasound in order to evaluate the presence of these lesions. GRT in these patients might also help preserving fertility.

Ginecomastia e hipogonadismo hipogonadotropo por tumor de células de Leydig: una causa poco frecuente de tumor testicular / Gynecomastia and hypogonadotropic hypogonadism caused by Leydig cell tumor: a rare cause of testicular tumor

Los tumores de células de Leydig son raros y suponen una pequeña proporción de neoplasias testiculares (1-3 %). La forma más frecuente de presentación es una masa indolora testicular o un hallazgo ecográfico incidental acompañado en más del 80 % de los casos de desórdenes hormonales. Los marcadores tumorales séricos son negativos y aproximadamente el 30 % de los casos presentan ginecomastia. El tratamiento de elección es la cirugía (orquiectomía ingui-nal) y el seguimiento postoperatorio será prolongado. El diagnóstico definitivo es histológico y se realizará durante o tras la cirugía. Entre los marcadores inmunohistológicos de tumores de células de Leydig se incluyen alfa inhibina, calretinina y melan A. La presencia de la subunidad alfa de inhibina mediante técnica de inmunohistoquímica, destaca la intensa positividad de las células tumorales en comparación con la del tejido sano circundante. La calretinina es más sensible pero menos específica que la inhibina. Melan A es un marcador moderadamente sensible y específico en la diferenciación de tumores del estroma del cordón sexual y como tal es un valor complementario a otros marcadores inmunohistoquímicos en la valoración de tumores de difícil diagnóstico. El interés de este caso es mostrar la complejidad de alteraciones clínicas asociadas a estos tumores, así como establecer un diagnóstico diferencial con otros tumores histológicos

Leydig cell tumors are rare and account for a small proportion of testicular neoplasms (1-3%). They most frequently present as a painless testicular mass or as an incidental ultrasound finding, accompanied by hormonal disorders in more than 80% of cases. Serum tumor markers are negative and approximately 30% of cases present gynecomastia. The treatment of choice is surgery (inguinal orchiectomy) with a long post-operative follow-up. The definitive diagnosis is histological, which will be carried out during or after surgery. The immunohistochemical markers of Leydig cell tumors include inhibin alpha, calretinin, and melan-A. The presence of the inhibin alpha subunit in immunohistochemical analysis shows intense positivity of tumor cells compared with the surrounding healthy tissue. Calretinin is more sensitive but less specific than inhibin. Melan-A is a moderately sensitive and specific marker of sex cord-stromal tumors, and, as such, complements other immunohistochemical markers in the assessment of tumors which are difficult to diagnose. The interest of this case is to show the complex pattern of clinical presentation of these tumors, and to establish a differential diagnosis with other testicular tumors

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Hipoplasia adrenal congénita ligada al cromosoma X: mutación missense de novo en el gen DAX-1 / X-linked adrenal hypoplasia congenita: Novel missense mutation of DAX-1 gene

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Adrenal hypoplasia congenita in identical twins.

We are presenting a monozygotic twin brothers presented at different ages with different presentations. Twin-A presented at age of 18 days with salt losing crisis. Investigations revealed high plasma renin with low-normal aldosterone. Adrenocorticotropic hormone, stimulation test revealed low 17-OH progesterone at 0 and 60 minutes. Adrenocorticotropic hormone level and serum cortisol were normal, which excluded initial impression of congenital adrenal hyperplasia. He was diagnosed to have isolated primary hypoaldosteronism. At age of 18 months, he was noticed to have hyperpigmentation of lips and gum. Adrenal failure was suspected, and hydrocortisone was added. Twin-B presented at 9 years and 6 months of age with adrenal crisis. Both were having unilateral undescended testes. Adrenal hypoplasia congenita (AHC) was suspected after his twin's presentation.  Molecular analysis for gene study for both of them revealed adrenal insufficiency, NR0B1 (DAX1) gene mutation. In conclusion, gene analysis is important for the diagnosis of AHC and for genetic counseling.

Identification of a novel mutation of NR0B1 in a patient with X-linked adrenal hypoplasia and symptomatic treatment.

BACKGROUND: X-linked congenital adrenal hypoplasia (X-linked AHC) is characterized by acute onset of primary adrenal insufficiency in infancy or early childhood and hypogonadotropic hypogonadism (HH) at puberty. Mutations in NR0B1, the gene located on Xp21.3 and encoding an orphan nuclear receptor named DAX1, are responsible for this disease. METHODS: The entire coding region of the NR0B1 gene of a 14-year-old X-linked AHC proband as well as his family members was sequenced. Clinical and endocrine evaluations with symptomatic treatment results were recorded. RESULTS: DNA sequencing revealed a missense mutation (c.383-384 insA) in exon 1, which resulted in a novel frameshift mutation, thereby resulting in a truncated protein (p.Leu129 Pro fs*137). The therapeutic trail with an observation period of 20 weeks showed an effective improvement in symptoms of hypogonadism with human chorionic gonadotropin (HCG) administration, including a rapid improvement of serum testosterone level, descending of testicles as well as enlargement of testicles and growth of penis. CONCLUSIONS: Our study identified a novel frameshift mutation of the NR0B1 gene in a proband with X-linked AHC/HH and further expanded the number of NR0B1 mutations reported in the literature. Moreover, the symptomatic treatment observation provided referential evidence in the treatment of X-linked AHC associated hypogonadism and bilateral inguinal cryptorchidism.

A novel DAX-1 (NR0B1) mutation in a boy with X-linked adrenal hypoplasia congenita.

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in DAX-1 (NR0B1) playing a key role in adrenal and reproductive development. CASE PRESENTATION: Herein we report a 2.5-year-old boy who presented with acute adrenal failure. Family history revealed unexplained death in three brothers of the patient's mother during infancy. Molecular analysis of the DAX-1 gene revealed the presence of a novel hemizygous mutation, c.870C>A in exon 1, leading to the formation of a premature stop codon. The same mutation was identified in the patient's mother. The truncated mutant protein is most likely misfolded, sequestered in the endoplasmic reticulum and therefore cannot bind to and activate its target DNA sequences in the nucleus. CONCLUSIONS: DAX-1 mutation must be considered when diagnosis of primary adrenocortical insufficiency is made, especially if there is a history of unexplained death of maternal male relatives.

[Recurrent anorexia and pigmentation of skin for more than two months in an infant].

A 2-month-old boy presented with adrenal insufficiency, impaired liver function, hypertriglyceridemia, significantly elevated creatine kinase and electrolyte disturbance. Microarray comparative genomic hybridization (aCGH) analysis test showed a pathogenic 8.7 Mb deletion in the short arm of chromosome X (Xp21.3 - p21.1) and confirmed the diagnosis of complex glycerol kinase deficiency (cGKD). He was treated with hydrocortisone, coenzyme Q10 and L-carnitine and was subsequently followed up for 4 years. His serum cortisol levels returned to normal one week later after treatment, but the serum creatine kinase, triglyceride and aminotransferase levels were progressively increased along with mental retardation and decreased muscular strength. cGKD is also named as Xp21 contiguous gene syndrome. The clinical manifestations of this disease include hypertriglyceridemia, congenital adrenal hypoplasia (AHC), Duchenne muscular dystrophy, and mental retardation. This case highlights the necessity to screen the serum triglyceride and creatine kinase levels in infants with suspected adrenal insufficiency.