Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations

Introduction X‐linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX‐1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure. Patients and methods We evaluated the clinical, endocrine and molecular characteristics of 12 AHC patients from 5 families diagnosed between 1984 and 2007 in Israel. Results Most of the boys (10/12) presented with signs of adrenal insufficiency such as salt wasting and failure to thrive during the neonatal period. Aldosterone deficiency usually preceded cortisol deficiency requiring early mineralocorticoid therapy. Serum cortisol levels in the first weeks of life varied from very low to high levels (<2·76 to >1776 nmol/l). Five boys showed signs of precocious sexual development during infancy and childhood, including enlargement of the penis and testes. In four patients the initial diagnoses were erroneous. Molecular analysis of the NR0B1 gene identified point mutations in six patients including a novel splice site mutation in one patient and his family (IVS1‐1G→C). Contiguous gene deletion was found in six patients from two families who manifested impaired mental development. Conclusions In X‐linked AHC caused by different molecular defects in NR0B1 gene, the clinical spectrum of the disease is quite variable and precocious sexual development is a prominent feature. Genetic testing is indicated in boys presenting with salt‐wasting with or without cortisol deficiency if congenital adrenal hyperplasia has been ruled out.     

Fréquence et déterminants de l’insuffisance surrénalienne biologique dépistée par le test au Synacthène à 250 μg lors du sevrage d’une corticothérapie prolongée. Étude chez 100 patients

Purpose

The frequency of adrenal insufficiency after a prolonged, continuous course of oral high-dose corticosteroids is poorly documented. We evaluated it retrospectively in our internal medicine department.

Methods

The patients were included between February 2000 and June 2007 and were administered a Synacthene^® 250 μg test (ST250) before tapering prednisone dose below 5 mg per day. A non-responsive test was defined by a cortisol increase below 18 μg/dL, 60 min after stimulation. We also studied the risk factors associated with biological adrenal insufficiency by a multivariate logistic regression analysis.

Results

Hundred patients were included (mean age: 61.5 ± 16.3 years). Mean initial dose of corticosteroids was 65.5 ± 112 mg/d. Forty-five patients failed to respond to the ST250. A normal ST250 was negatively associated with a duration of corticosteroids therapy longer than 19.5 months (OR = 0.38 [0.15–0.94]; p = 0.04) and positively with an age over 63.5 years (OR = 2.5 [1.1–6.4]; p = 0.05). Two patients experienced a clinical adrenal insufficiency crisis.

Conclusion

Biological adrenal insufficiency is very common after a prolonged course of oral high-dose corticosteroids. The risk does not seem to increase with age. The clinical benefit of a systematic ST250 at the time of corticosteroids withdrawal followed by hydrocortisone substitution if the test is non responsive remains unknown, and this practice is still a matter of debate.     

Hémorragie surrénalienne bilatérale révélant une hyperhomocystéinémie

Introduction

Bilateral adrenal hemorrhage remains a rare disease. It has several etiologies, and clinical presentation is not specific.

Case report

We report a 45-year old man without known prothrombotic factor who presented with acute left sided abdominal pain left revealing a bilateral adrenal hemorrhage. The diagnostic work-up identified a significant hyperhomocysteinemia associated with a previously undiagnosed homozygous mutation of the 5,10 methylene–tetrahydrofolate reductase gene. The outcome was associated with the occurrence of an adrenal insufficiency.     

Late-onset X-linked adrenal hypoplasia (DAX-1, <Emphasis Type="Italic">NR0B1</Emphasis>): two new adult-onset cases from a single center

Purpose

DAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo–pituitary–gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood.

Methods

We describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital.

Results

Case 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775T?>?C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836C?>?T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members.

Conclusions

We describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear.

     

Maladie de Niemann-Pick de type B : description clinique de trois cas familiaux

Introduction

The Niemann Pick disease type B is a rare deficiency in sphingomyelinase activity, autosomal recessively inherited.

Case reports

We report three patients (two men, one woman) of the same family, who showed pulmonary and hepatosplenic lesions, usually present in the disease but also adrenal gland lesions confirmed by tomodensitometry.

Conclusion

The current treatment of Niemann Pick disease is purely symptomatic awaiting the use of enzymatic replacement therapy which has been successfully experimented in animal model.     

Are human male patients with DAX1/NR0B1 mutations infertile?

DAX-1 stands for Dosage sensitive sex-reversal, Adrenal hypoplasia congenital (AHC), on the X chromosome. DAX-1 mutations usually cause primary adrenal insufficiency or congenital adrenal hypoplasia in early childhood and hypogonadotropic hypogonadism (MIM # 300200). DAX-1 protein is necessary to maintain normal spermatogenesis. In humans, male fertility has been studied in few patients carrying DAX-1 mutations. Cases of azoospermia have been reported, as well as unsuccessful gonadotropin treatments. The clinician should be informed that TESE–ICSI technique carries a potential hope to father non-affected children, as shown in this review.     

A Case Report of Adrenocortical Adenoma Mimicking Congenital Adrenal Hyperplasia in a Young Girl

Adrenal cortical tumors are rare in children. Secondary tumors associated with untreated congenital adrenal hyperplasia (CAH) have also been reported in pediatric population. It is difficult for pediatricians to differentiate these 2 lesions.We described a 4.5-year-old girl who presented with symptoms and signs of virilization. Bone age was 9.5 years. Genetic analysis of CYP21A2 and CYP11B1 revealed a heterozygous mutation of CYP11B1 at c.1157C>T (A386V). No germline p53 gene mutation including R337H was detected.The patient was first misdiagnosed as CAH and treated with hydrocortisone for 3 months. Diagnosis of an adrenal cortical tumor was confirmed by laboratory data and abdominal computed tomography. After resection of the tumor, serum steroids normalized and clinical signs receded. The child received no additional treatment and remains disease free after 12 months of close observation. Histological examination showed neoplasia cells with predominantly eosinophilic cytoplasm and few atypical mitotic figures. The proliferation-associated Ki-67 index was <1% detected by immunohistochemistry.Neoplasm is a rare but significant cause of precocious puberty (PP). The possibility of neoplasms should always be considered early to avoid delayed cancer diagnosis and treatment in cases of PP.     

Amylose cardiaque : à propos d’une série de 14 patients,description et facteurs pronostiques

Purpose

Cardiac amyloidosis is rare. The objective of this study was to report on a case series of 14 patients with cardiac amyloidosis and to study the prognostic factors.

Methods

Monocentric retrospective study of all adult patients who presented with cardiac amyloidosis, diagnosed at the Georges-Pompidou European hospital in Paris between 2003 and 2011.

Results

Fourteen patients were identified (10 men and four women). Median age at diagnosis was 66.5 years. Twelve patients were diagnosed with AL amyloidosis, one with AA amyloidosis, and one with transthyretin amyloidosis. All patients presented cardiac manifestations: heart failure (n = 9), rhythm disorders (n = 6). Eight patients presented extra-cardiac manifestations of amyloidosis: renal (n = 8), gastrointestinal (n = 5). Troponin serum level was increased in eight patients and BNP level was superior to 400 pg/L in 12 patients. When performed, the cardiac magnetic resonance imaging (MRI) showed, in six patients out of seven, chamber dilatation, concentric hypertrophy or late enhancement. Among patients with cardiac failure at diagnosis (n = 9), seven died with a median survival of 1 month duration. Factors of poor prognosis were, in our study, heart failure, elevated levels of troponin and BNP, and the AL amyloidosis subtype.

Conclusion

Cardiac amyloidosis, especially the AL type, has a very poor prognosis, essentially because of an underlying multiple myeloma and heart failure.     

Lupus hepatitis: a case series of 12 patients

Purpose

Several liver manifestations have been reported in systemic lupus erythematosus (SLE) and are usually non specific. We report on our experience of lupus hepatitis.

Methods

A retrospective monocenter study of 73 patients with SLE. The diagnosis of lupus hepatitis was established after exclusion of other causes of hepatitis and hepatic vein thrombosis.

Results

Liver involvement was noted in 12 patients (16.4%). There were nine female and three male patients; the mean age of these patients was 29 years. In seven patients liver involvement was concurrent with the diagnosis of SLE and it occurred later during an exacerbation of the disease in the five remaining patients. In all patients, liver manifestations were associated with other organ involvement. Clinical manifestations were: hepatomegaly (n = 4), jaundice (n = 4), abdominal pain (n = 3), ascitis (n = 2), portal hypertension (n = 1) and hepatic failure with encephalopathy (n = 1). Elevated liver enzyme was noted in 11 cases and liver cholestasis in eight cases. Presence of anti-ribosomal P antibodies was noted in one case. Liver biopsy was performed in five patients, and revealed chronic active hepatitis in three cases, chronic hepatic granulomas in one case and nonspecific inflammation in one case. The outcome was favorable in 11 patients without relapse, and one patient died of encephalopathy and liver failure.

Conclusion

Liver involvement associated with SLE is not uncommon. It is frequently asymptomatic and limited to liver test abnormalities. The role of anti-ribosomal P autoantibodies remains uncertain.     

Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: Long term follow-up

Context

Bilateral adrenalectomy has been recently proposed as a surgical treatment option for patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. There is however little documented data about the long-term efficiency and potential side effects of this treatment. Patients with 11β-hydroxylase deficiency (11βHD) have been also concerned by this new approach.

Objective

Our objective was to describe our experience with bilateral adrenalectomy as a treatment of severe hypertension in a patient with 11βHD deficiency and to report the long term follow-up (72 months) results after surgery.

Patient and Intervention

A 22-year-old genetically female patient with 11βHD deficiency was raised as a male because of severe pseudohermaphroditism. The patient has been managed by conventional steroid suppressive therapy and antihypertensive drugs with limited success; hypertension remained uncontrolled and led to severe complications. Bilateral adrenalectomy was offered to him.

Results

The intervention was followed by immediate blood pressure normalization and resulted in remarkable clinical improvement. Good compliance with glucocorticoid and androgen substitutive therapies was noted. However, a high 11-deoxycortisol, presumably due to non-ovarian ectopic adrenal rests was noted 24 months after surgery.

Conclusion

Bilateral adrenalectomy is a safe and efficient method of managing CAH with selected patients. Long-term clinical and biochemical follow-up of patients with CAH treated by bilateral adrenalectomy is needed to earlier detect ectopic adrenal rests.     

Le degré de l’insuffisance rénale chronique est associé aux taux de cytokines pro-inflammatoires, à l’hyperhomocystéinémie et au stress oxydant

Aim

To evaluate pro-inflammatory cytokines, homocysteinemia and markers of oxidative status in the course of chronic renal failure.

Patients and methods

One hundred and two patients (male/female: 38/64; age: 45 ± 07 years) with chronic renal failure were divided into 4 groups according to the National Kidney Foundation classification. They included 28 primary stage renal failure patients, 28 moderate stage renal failure, 28 severe stage renal failure and 18 end stage renal failure. The inflammatory status was evaluated by the determination of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and total homocysteine. Pro-oxidant status was assessed by assaying thiobarbituric acid reactive substances, hydroperoxides, and protein carbonyls. Antioxidant defence was performed by analysis of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase.

Results

Inflammatory markers were elevated in the end stage renal failure group compared to the other groups (P < 0.001). Indeed, an increase in thiobarbituric acid reactive substances, hydroperoxides and protein carbonyls was noted in the end stage renal failure group in comparison with the other groups (P < 0.001), while the levels of antioxidants enzymes activity were decreased in the study population (P < 0.001).

Conclusion

Impaired renal function is closely associated with the elevation of inflammatory markers leading to both increased markers of oxidative stress and decreased antioxidant defense.     

Prolonged activation of the hypothalamus-pituitary-gonadal axis in a child with X-linked adrenal hypoplasia congenita

X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder of the human adrenal cortex that is caused by a mutation of the DAX-1 gene, a member of the nuclear hormone receptor superfamily. Hypogonadotrophic hypogonadism is frequently associated with this disease and the DAX-1 mutation is known to impair gonadotrophin production by acting at both the hypothalamic and pituitary levels. However, three recent studies reported that the hypothalamic-pituitary-gonadal axis was active in six infants with AHC, suggesting that a difference exists in the central regulation of hypothalamic-pituitary-gonadal activity between infant boys and pubertal boys. To determine the effect of the DAX-1 gene mutation on the axis in early childhood, we measured testosterone, LH, and FSH and performed LH-releasing hormone tests on a boy with AHC from birth to 3 years of age. Surprisingly, our findings showed that the axis was active from the infantile period to 3 years of age. This delayed initiation of the prepubertal pause, or prolonged activation of the axis, indicates that the DAX-1 gene is related to the control mechanism of the prepubertal restraint of gonadotrophin secretion.     

Fibrose(s) rétropéritonéale(s) : stratégie diagnostique,pathologies associées et suivi à long terme d’une cohorte française

Purpose

Retroperitoneal fibrosis (RPF) is a rare disease with an expanding etiologic spectrum. We aimed to analyze non-invasive diagnosis strategy, associated disorders, monitoring, treatment and prognosis.

Methods

Retrospective cohort study in a single tertiary center.

Results

Eighteen RPF cases (11 males) followed between 1996 and 2009 were reviewed. Blood CRP level was high in all cases before treatment. CT scan, associated or not with MRI or 18-FDG PET-scan, confirmed the diagnosis in 15 patients. Histological analysis of a surgical biopsy specimen was performed in only three cases. Ten patients suffered retroperitoneal fibrosis secondary to systemic vasculitis (granulomatosis with polyangeitis, n = 1, Takayasu aortitis, n = 2), systemic fibrosis with Riedel thyroiditis (n = 1) and atheromatous periaortitis (n = 6). Fifteen patients were treated with corticosteroids with a mean treatment duration of 60 months (12–228). Dependency to corticosteroids was recorded in ten patients. Patients with fibrosis related to vasculitis were younger, had a higher CRP level, more frequent corticosteroid dependency and a higher relapse rate. Relapses were successfully treated with steroids. Immunosuppressive treatment was only prescribed in the setting of systemic vasculitis. No patient died, after a 6 ± 2 years follow-up. Late relapses could occur, sometimes years after steroid therapy cessation.

Conclusion

In our study, RPF occurred as a secondary disorder in 60% of the cases. Disease extension, relapse rate and treatment response varied according to the underlying cause of RPF, pleading for an extensive and systematic initial assessment. Since no death or end-stage renal insufficiency was observed, RPF might be considered as a steroid-sensitive and benign disorder.