Endocrine and molecular investigations in a cohort of 25 adolescent males with prominent/persistent pubertal gynecomastia.

Pubertal gynecomastia is a common condition observed in up to 65% of adolescent males. It is usually idiopathic and tends to regress within 1-2 years. In this descriptive cross-sectional study, we investigated 25 adolescent males with prominent (>B3) and/or persistent (>2 years) pubertal gynecomastia (P/PPG) to determine whether a hormonal/genetic defect might underline this condition. Endocrine investigation revealed the absence of hormonal disturbance for 18 boys (72%). Three patients presented Klinefelter syndrome and three a partial androgen insensitivity syndrome (PAIS) as a result of p.Ala646Asp and p.Ala45Gly mutations of the androgen receptor gene. The last patient showed a 17α-hydroxylase/17,20-lyase deficiency as a result of a compound heterozygous mutation of the CYP17A1 gene leading to p.Pro35Thr(P35T) and p.Arg239Stop(R239X) in the P450c17 protein. Enzymatic activity was analyzed: the mutant protein bearing the premature stop codon R239X showed a complete loss of 17α-hydroxylase and 17,20-lyase activity. The mutant P35T seemed to retain 15-20% of 17α-hydroxylase and about 8-10% of 17,20-lyase activity. This work demonstrates that P/PPG had an endocrine/genetic cause in 28% of our cases. PAIS may be expressed only by isolated gynecomastia as well as by 17α-hydroxylase/17,20-lyase deficiency. Isolated P/PPG is not always a 'physiological' condition and should thus be investigated through adequate endocrine and genetic investigations, even though larger studies are needed to better determine the real prevalence of genetic defects in such patients.

[Uncommon neonatal case of hypoglycemia: ACTH resistance syndrome]. / Hypoglycémie néonatale sévère et récidivante sans perte de sel révélatrice d'un syndrome de résistance à l'ACTH.

Monitoring of blood glucose is usually reported to reduce the risk of hypoglycemia in term newborns with high risk factors and for prematurity in neonatal intensive care unit patients. Differential diagnosis has rarely been discussed. In the eutrophic term newborn, hypoglycemia remains rare and an etiological diagnosis must be made. Intensive management of neonatal hypoglycemia is required to prevent neurodevelopmental defects. Without evident cause or if hypoglycemia persists, a systematic review of possible causes should be made. We report isolated glucocorticoid deficiency diagnosed in an infant at 10 months of age. This boy had neonatal hypoglycemia and mild jaundice that had not been investigated. During his first 9 months of life, he presented frequent infections. At 10 months of age, febrile seizures occurred associated with shock, hypoglycemia, hyponatremia, mild hyperpigmentation, and coma. He was diagnosed with hypocortisolemia and elevated ACTH levels. Brain injury was revealed by MRI after resuscitation, with hypoxic-ischemic and hypoglycemic encephalopathy. The molecular studies demonstrated the presence of p.Asp107Asn and previously unreported frameshift p.Pro281GlnfsX9 MC2R gene mutations. A substitutive hormone therapy was provided and during a follow-up of 12 months no adrenal crisis was noted. We report an unusual case of familial glucocorticoid deficiency with severe neurological injury. This case demonstrates the importance of an appropriate etiological diagnosis in neonatal hypoglycemia.

Biological assessment of abnormal genitalia.

Biological assessment of abnormal genitalia is based on an ordered sequence of endocrine and genetic investigations that are predicated on knowledge obtained from a suitable history and detailed examination of the external genital anatomy. Investigations are particularly relevant in 46,XY DSD where the diagnostic yield is less successful than in the 46,XX counterpart. Advantage should be taken of spontaneous activity of the pituitary-gonadal axis in early infancy rendering measurements of gonadotrophins and sex steroids by sensitive, validated assays key to assessing testicular function. Allied measurement of serum anti-Müllerian hormone completes a comprehensive testis profile of Leydig and Sertoli cell function. Genetic assessment is dominated by analysis of a plethora of genes that attempts to delineate a cause for gonadal dysgenesis. In essence, this is successful in up to 20% of cases from analysis of SRY and SF1 (NR5A1) genes. In contrast, gene mutation analysis is highly successful in 46,XY DSD due to defects in androgen synthesis or action. The era of next generation sequencing is increasingly being applied to investigate complex medical conditions of unknown cause, including DSD. The challenge for health professionals will lie in integrating vast amounts of genetic information with phenotypes and counselling families appropriately. How tissues respond to hormones is apposite to assessing the range of genital phenotypes that characterise DSD, particularly for syndromes associated with androgen resistance. In vitro methods are available to undertake quantitative and qualitative analysis of hormone action. The in vivo equivalent is some assessment of the degree of under-masculinisation in the male, such as an external masculinisation score, and measurement of the ano-genital distance. This anthropometric marker is effectively a postnatal readout of the effects of prenatal androgens acting during the masculinisation programming window. For investigation of the newborn with abnormal genitalia, a pragmatic approach can be taken to guide the clinician using appropriate algorithms.

[Four cases of aldosterone synthase deficiency in childhood]. / Déficit en aldostérone-synthase : 4 observations pédiatriques.

Neonatal salt-wasting syndromes are rare but potentially serious conditions. Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types I and II. In type I, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type II, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. We report on four patients with isolated hypoaldosteronism. In 2 of them, who were recently diagnosed with aldosterone synthase deficit, we discuss the symptoms and treatment. The 2 other patients are now adults. We discuss the long-term outcome, the quality of adult life, aldosterone synthase deficits, as well as the pathophysiology and molecular analysis.

[Acute disseminated encephalomyelitis after tetanus vaccination of a pregnant woman in Senegal]. / Encéphalomyélite aiguë disséminée après vaccination antitétanique : une observation chez une femme enceinte au Sénégal.

Although neurological complications have been described after tetanus vaccinations, they are rare. The authors report a case of acute disseminated encephalomyelitis (ADEM) in a 28-year-old pregnant woman at a gestational age of 10 weeks, admitted 15 days after a tetanus vaccination, with spastic tetraplegia and sphincter disturbances. Corticosteroid treatment led to partial recovery of the neurological deficit. Differential diagnosis of infectious and demyelinating diseases of the central nervous system is difficult in view of clinical and laboratory aspects of post-vaccination ADEM. Without any specific diagnostic markers, the clinical examination, magnetic resonance imaging and negative etiological findings were key to this diagnosis. Medical staff must bear in mind the possible complications of this vaccine.

[Myelopathy due to Schistosoma mansoni]. / Myélopathie à Schistosoma mansoni.

INTRODUCTION: Neurological complications of schistosomiasis remain exceptional even in hyperendemic area. CASE REPORT: We report a 26-year-old Senegalese man, without past medical history, who was admitted for spastic paraplegia, acute retention of urine, and pain in low back and lower limbs. The final diagnosis was spinal cord schistosomiasis. Diagnosis was based on the endemic context, MRI medullar conus imaging, schistosoma serology in cerebrospinal fluid and blood, and the absence of other cause of myelopathy. Treatment was based on praziquantel, corticosteroids and physiotherapy. The outcome was favorable after a 2-year follow-up. CONCLUSION: Schistosomiasis should be included in the differential diagnosis of myelopathy in patients living actually, or even traveled in the past, in endemic tropical areas.

Decrease of anti-Mullerian hormone in genetic spermatogenic failure.

The aim of this study was to compare anti-Mullerian hormone (AMH) plasma levels in patients with azoospermia according to the physiopathology. In a prospective clinical study from April 2008 to March 2009 in University Hospital, we measured AMH levels in 49 consecutive patients with azoospermia. AMH plasma levels were correlated with FSH, inhibin B, bioavailable testosterone plasma levels and testicular volume and compared between nonobstructive azoospermia (NOA) and obstructive azoospermia (OA) and within four physiopathological subgroups of NOA: genetic, cryptorchidism, cytotoxic and unexplained. AMH, FSH, inhibin B, bioavailable testosterone plasma levels and testicular volumes were all related to each other. AMH plasma levels were lower in NOA relatively to OA. Lowest values were observed in cases of genetic NOA and on the other hand, the values observed in case of cytotoxic NOA were as high as the values observed in OA. FSH, inhibin B, bioavailable testosterone and testicular volume were not different between genetic and cytotoxic NOA. These results suggest that the decrease in AMH plasma levels is related to the origin of NOA, with low values in genetic NOA and values similar to OA in cytotoxic NOA. Further studies will be useful to understand the fine regulation of AMH production.

REMOVAL: Pelvic MRI in a 17-year-old XY girl with 5-alpha reductase deficiency and a homozygous Gly115Asp mutation in SRD5A2.

This article has been removed: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been removed at the request of the Editor-in-chief and the corresponding author for legal reasons regarding the patient consent.

[Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature]. / L'hypoplasie surrénale congénitale de type anencéphalique: deux cas avec anomalies hypophysaires, sans mutation de DAX-1 et SF-1 et revue de la littérature.

Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

Three novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11Beta-hydroxylase deficiency in a moroccan population.

BACKGROUND/AIMS: Steroid 11beta-hydroxylase deficiency (11OHD), the second cause of congenital adrenal hyperplasia (CAH), accounts only for 5% of all CAH. To date, only 51 different mutations have been reported with poor clinical and biological data. Most of them could be considered as private mutations except one, p.R448H, identified especially in Moroccan Jews but also in Caucasian patients. As two other CYP11B1 mutations have a high incidence in Tunisian patients, we report from another Maghreb population the clinical, follow-up and molecular genetics of 5 Moroccan patients with classical 11OHD. METHODS: Patients belonging to 3 families were recruited on clinical data. The diagnosis was confirmed by 11-deoxycortisol determination. Sequencing of the CYP11B1 gene and molecular modeling were performed. RESULTS: Clinical, hormonal and follow-up data were consistent with a severe form of 11OHD. Gender reassignment and evolution of hypertension were discussed. Three novel mutations, p.Ala259Asp, p.Gly446Val and IVS5+2T>G were identified. As each patient was homozygous for one mutation, we could deduce from their phenotype and our modeling studies that the p.Gly446Val mutation was more severe than p.Ala259Asp. CONCLUSION: This study shows a good correlation between phenotype and genotype. Each CYP11B1 mutation is new and private, contrasting with the high incidence of two Tunisian mutations.

Only two mutations detected in 15 Tunisian patients with 11ß-hydroxylase deficiency: the p.Q356X and the novel p.G379V.

Steroid 11ß-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. The 11ß-hydroxylase enzyme is encoded by the CYP11B1 gene and mutations in this gene are responsible for this disease. The aim of this study was to characterize mutations in the CYP11B1 gene and to determine their frequencies in a cohort of Tunisian patients. The molecular genetic analysis was performed by direct nucleotide sequencing of the CYP11B1 gene in 15 unrelated Tunisian patients suffering from classical 11ß-hydroxylase deficiency. Only two mutations were detected in homozygous state in the CYP11B1 gene of all patients, the p.Q356X in exon 6 (26.6%) and the novel p.G379V in exon 7 with large prevalence (73.3%). This is the first report of screening for mutations of CYP11B1 gene in the Tunisian population and even in the Arab population.

Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.

CONTEXT: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with genotype/phenotype relationships for common mutations. Novel mutations of the CYP21A2 gene must be well studied to propose right genetic counseling for patients. OBJECTIVE: Thirteen CYP21 mutations have been studied. A detailed description of phenotype was performed for all mutations (p.I77T, p.L167P, p.I230T, p.R233K, p.G291S, p.G292D, p.E320K, p.R341P, p.R354H, p.R369W, p.R408C, p.G424S, and p.R426H). In vitro and in silico studies were performed only for those not previously described (p.L167P, p.I230T, p.R233K, p.G292D, p.E320K, and p.R369W). RESULTS: Regarding phenotype, patients with 10 of these mutations had a classical form. A patient with isolated p.I230T presented with nonclassical form and a patient with the association p.I230T + p.V281L in cis presented with a more severe phenotype. The p.R233K mutation was detected in a carrier partner. A patient with p.R369W presented with an intermediate form. Functional studies showed that all mutations except p.I230T and p.R369W decreased enzyme activity more than p.P30L: severity of p.R369W was intermediate between p.P30L and p.V281L, and finally p.I230T was less severe than p.V281L. Mutation analysis in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, severe mutations being implicated in important functional domains of the protein. CONCLUSION: According to phenotype and functional studies, 11 of the mutations described, except the isolated p.R369W and p.I230T, may be responsible for a severe phenotype underlying the necessity to manage children having them. The p.I230T is a nonclassical mutation, and for the p.R369W, we need more cases to precise its severity.

Detection and management of late-onset 21-hydroxylase deficiency in women with hyperandrogenism.

Moderate forms of 21-hydroxylase deficiency (D21OH-NC), the so-called non-classical or late-onset forms are a frequently reported cause of hyperandrogenism in women [1-5]. The purpose of this collective and synthetic work was to provide the endocrinologist, gynecologist and dermatologist with consensual information so as to detect the maximum cases with acceptable cost-benefit ratio and to define the main lines of optimal patient management, given the data currently available in medical literature.

Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia due to 11beta-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 11beta-hydroxylase deficiency (11betaHD) 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 11betaHD 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 11betaHD 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.

p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency.

CONTEXT: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with good genotype/phenotype relationships for common mutations. To determine the severity of rare mutations is essential for genetic counseling and better understanding of the structure-function of the cytochrome P450c21. OBJECTIVE: The p.H62L mutation was the most frequent of 60 new mutations detected in 2900 steroid 21-hydroxylase deficiency patients, either isolated or associated on the same allele with a mild mutation (p.P453S, p.P30L, or partial promoter). Because phenotypes seemed to differ between patients with isolated or associated p.H62L, a detailed phenotype description and functional studies were performed. RESULTS: Regarding phenotype, patients with isolated p.H62L had a nonclassical form, whereas patients with the association p.H62L + mild mutation had a simple virilizing form. Functional studies showed that p.H62L reduced the conversion of the two substrates, progesterone and 17-hydroxyprogesterone, in the same way as the mild p.P453S; the association p.H62L + p.P453S decreased enzymatic activity more strongly while conserving residual activity at a level intermediate between p.P453S and p.I172N. This suggested that p.H62L was a mild mutation, whereas a synergistic effect occurred when it was associated. Analysis of p.H62L in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, the H62 being located in a domain implied in membrane anchoring. CONCLUSION: According to phenotype and functional studies, p.H62L is a mild mutation, responsible for a more severe phenotype when associated with another mild mutation. These data are important for patient management and genetic counseling.

[Gayet-Wernicke's encephalopathy. A study of 13 cases observed in a refugee population hospitalized at the Conakry Teaching Hospital]. / Encéphalopathie de Gayet-Wernicke. Etude de 13 observations dans une population de patients réfugiés hospitalisés pour affections neurologiques au CHU de Conakry.

The authors report 13 cases of Gayet-Wernicke's encephalopathy observed in 13 patients of a refugee population. 11 presented the classical triad: oculomotor signs, cerebral ataxia and state of confusion and in 2 patients, only 2 symptoms were noted. The etiological factors: chronic alcoholism, malnutrition, uncontrollable vomiting, HIV and tuberculosis were identified. The outcome was evaluated on the basis of the disappearance of symptoms after treatment with 500 mg of thiamine in 7 patients, 1 death and 5 patients progressed toward Korsakoff amnesic syndrome.

Cosegregation of a novel homozygous CYP11B1 mutation with the phenotype of non-classical congenital adrenal hyperplasia in a consanguineous family.

We report a novel missense mutation of CYP11B1 causing non-classical 11beta-hydroxylase deficiency in 3 members of a consanguineous Turkish family. Two siblings presented with clinical evidence of precocious pseudopubarche. Biochemistry suggested 11beta-hydroxylase deficiency and genetic analysis revealed that they were homozygous for the missense mutation L489S within exon 9 of the CYP11B1 gene. The unaffected parents were heterozygotes for the same mutation. In addition, a paternal aunt of the affected siblings presenting with primary infertility and mild hirsutism was found to have the same homozygous mutation. This is the first report of a homozygous mutation in non-classical congenital adrenal hyperplasia that cosegregates with clinical phenotype. The significance of the missense mutation L489S in CYP11B1 is further supported by the conservation of leucine at position 489 in CYP11 genes in eleven other species. Molecular modelling of the enzyme suggests that the mutation L489S in CYP11B1 may alter the enzyme's substrate-binding affinity. These findings suggest that this homozygous mutation affects 11beta-hydroxylase function, resulting in the clinical features of non-classical adrenal hyperplasia in this family.

Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment.

OBJECTIVE: To analyze the clinical and histological findings in boys with bilateral anorchia and the response to testosterone treatment on penis length. STUDY DESIGN: Patients were divided into two groups according to the absence (group A, n = 29) or the presence (group B, n = 26) of palpable intrascrotal or inguinal mass at first clinical examination. RESULTS: A micropenis was found in 46% of patients (n = 24) with a similar proportion in both groups. Testosterone treatment induced a mean penis length gain of 1.9 +/- 1.3 SDS (standard deviation score). However, micropenis persisted in six patients. Histological examination (n = 18) confirmed the absence of any testicular structure with deferent ducts being present unilaterally or bilaterally in all but three patients. In these three patients, a hemorrhagic testis, probably as a result of a mechanical torsion, was found. CONCLUSIONS: The presence of isolated micropenis in almost half of patients with bilateral anorchia strongly suggests that the testicular damage frequently occurs during the second half of gestation after male sexual differentiation. In most cases, testosterone treatment stimulates the penile growth. Although the pathogenesis of bilateral anorchia may be heterogeneous, our study suggests that gonads may have been functionally abnormal before they disappeared, and suggests that some patients have an intrinsic endocrine disorder.

[Clinical and tomographic aspects of 29 cases of phakomatosis in Guinea]. / Aspects clinique et scannographique de 29 observations de phacomatoses en Guinée.

The purpose of this report is to describe 29 cases of phakomatosis including 18 cases of tuberous sclerosis (Bourneville) and 11 cases of neurofibromatosis (von Recklinghausen) observed over a 10-year period at the Neurology Department of the University Hospital Centre in Conakry, Guinea. Findings during this period were consistent with those classically reported in the literature: high frequency of advanced skin lesions coalescing into massive tumours, occurrence of seizures of all types and development of a wide variety of complications as a result of late diagnosis. Our experience underscores the need for follow-up and surveillance of these patients by somatic studies based on neurological, ophthalmologic and tomographic data depending on clinical findings.