Genomic basis of syndromic short stature in an Algerian patient cohort.

Short stature is one of the most common reasons for a referral to the pediatric endocrinology clinic. Thousands of patients with short stature are assessed annually at the Department of Endocrine and Metabolic Diseases (DEMD) at Bab el Oued University Hospital in Algiers, Algeria. However, diagnostic rates in patients with syndromic short stature are not optimal due to the unavailability of next generation sequencing (NGS) technology. Here, we enrolled 10 Algerian patients with syndromic short stature in a pilot study to test the impact of genetic and genomic approaches in the DEMD. Using a combination of two different NGS modalities, namely exome sequencing and the Mendeliome (TruSight™ One sequencing panel) along with single gene testing, we were able to establish a confirmed molecular diagnosis in 7/10 patients (70%) and to identify strong likely disease-causing variants in a further two patients. Novel variants in NPR2 and VPS13B were identified. Using copy number variation analysis on the exome data, we also identified a de novo deletion of the short arm of chromosome X. These definitive diagnoses have made a substantial impact on patient treatment, management and genetic counseling. Genomic testing has the ability to transform clinical practice, and is an essential diagnostic tool in any tertiary pediatric clinic, particularly in resource limited settings.

The importance of genetic study and long-term management in patients with bilateral pheochromocytomas.

Tumors secreting catecholamines, such as pheochromocytomas and paragangliomas, are rare and life-threatening, due to their complications. They can be sporadic or occur in genetic syndromes, such as von Hippel-Lindau in which pheochromocytomas are observed in 10 to 20%. We report a case of a 42 years old male, who was sent in 2016 to our department for neurological symptoms related to cerebellar and central vestibular syndromes. His medical history revealed that at 8 years old he was operated for a symptomatic bilateral pheochromocytoma discovered by adrenergic symptoms and high blood pressure. Cerebral MRI showed intra- and extra-axial, supra- and infratentorial lesions causing supratentorial hydrocephalus associated with leptomeningeal dissemination deemed to be hemangioblastomas. One year later the patient started complaining of chronic diarrhea. The abdominal CT revealed three pancreatic tumors with radiological signs of pancreatic neuroendocrine tumors (PNETs) and a 12 mm mesenteric nodule presenting as a homogenously and typical for NET. The largest PNET had intensive fixation on octreotide scintigraphy. The association of pheochromocytomas, hemangioblastoma and pancreatic neuroendocrine tumors highlighted the diagnosis of VHL syndrome. The family history proved positive in a sibling with bilateral pheochromocytoma in infancy, retinal hemangioblastomas and cerebral hemangioblastoma. Genetic testing would have been useful, but in our case, it was lacking due to poor socio-economic conditions of the patient and absence of genetic testing in public hospitals.

Feminizing Adrenocortical Carcinoma Without Gynecomastia.

Malignant feminizing adrenocortical tumors are exceedingly rare. Their main presentation is gynecomastia. In these estrogen secreting tumors (with or without other adrenocortical hormones) lack of gynecomastia is exceptional as in our case. A 44-year-old man presented with abdominal pain. Radiological assessment revealed a tumor measuring 120 × 95 mm in the retroperitoneal area with numerous metastases. Pathological examination pleaded for an adrenal origin with a Weiss's score of 5. Six months later, the tumor relapsed, and he had a second surgery and was sent for hormone assessment. Clinical examination showed a skinny man with severe fatigue. He had no Cushingoid features. Gynecomastia and galactorrhea were absent. Penile length, testicular volume, and body hair growth were normal. Several cutaneous nodules were present. Biological assessment showed high morning plasma cortisol, which failed to be suppressed by treatment with 2 mg dexamethasone. Plasma estradiol and 17OH progesterone levels were high, but his testosterone levels were low. Radiological exploration showed numerous metastases: pleural, pulmonary, retroperitoneal, and abdominal. He was treated with classical chemotherapy, but he died four months after diagnosis.

Management of prolactinomas: a survey of physicians from the Middle East and North Africa.

BACKGROUND: Prolactinomas are the commonest functional tumors of the pituitary gland. There are still controversies regarding medical therapy in specific clinical situations. Patients may be managed by different specialists in the Middle East and North Africa (MENA) region and no data exist on patterns of clinical management. OBJECTIVES: To ascertain the diagnostic and therapeutic approaches to prolactinomas among relevant professionals from the MENA region. METHODS: An online survey of a large sample of physicians was conducted. The questionnaire covered various aspects of diagnosis and treatment of prolactinomas. 468 respondents were included; 36 % were endocrinologists; 49 % worked in public facilities and 81 % graduated more than 10 years. 40 and 30 % would have seen 1-5 and more than 5 suspected or confirmed prolactinomas over a 6 months period, respectively. RESULTS: Regarding the diagnosis, 30 % of the respondents considered that prolactin levels <100 ng/ml exclude the presence of a prolactinoma. 21 % of respondents considered prolactin levels >250 ng/ml compatible with macroprolactinomas only, whereas others accepted this to be compatible also with microprolactinomas, macroprolactinaemia and drug-induced hyperprolactinemia (50, 42 and 36 % respectively). 71 % of respondents favored the screening for macroprolactin in asymptomatic individuals with hyperprolactinemia. Regarding the treatment, 84 % of respondents would treat microprolactinomas even in the absence of symptoms whereas 72 % of the respondents would treat microprolactinomas only if symptoms exist. 60 and 49 % of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas and microprolactinomas respectively. Similar proportions had no preference of either cabergoline or bromocriptine as the best treatment for macroprolactinoma (27 %) and microprolactinomas (32 %). 46 and 75 % of respondents favored treatment withdrawal 2-3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively whereas 10 % of respondents withdraw treatment after menopause in either case. 94 % of respondents considered medical therapy as the primary treatment for microprolactinomas. In case of pregnancy, 49 % considered bromocriptine as the drug of choice for women who wish to become pregnant. 65 and 38 % of respondents advocated discontinuation of treatment with dopamine agonists in patients with microprolactinomas and macroprolactinomas, respectively. Finally, 48 % would allow breast-feeding without restriction, 28 % would restrict it to patients with microprolactinomas and 25 % would not recommend it for women with prolactinomas. CONCLUSIONS: This is the first study of the clinical management of prolactinomas in the MENA region. Some of the practices are not in line with the latest Endocrine and Pituitary Societies guidelines. These warrant further discussions of contemporary guidelines in regional forums.

Microangiopathy and pregnancy.

Diabetic microangiopathy is a frequent complication of longstanding diabetes mellitus. Micro vascular lesions may have severe implications for both maternal and foetal health. Patients with advanced underlying lesions are at increased risk of progression during pregnancy. Severe retinal lesions can progress during pregnancy and one year after delivery. Poor glycaemic control prior to conception and rapid improvement during pregnancy are other risk factors of progression. Treatment of lesions with high risk of progression and progressive blood glucose lowering in the preconception period can improve the prognosis. Diabetic nephropathy predisposes to preeclampsia, premature delivery, intrauterine growth retardation and perinatal mortality. Patients with elevated creatinine levels are at increased risk of permanent impairment of kidney function. These patients should be closely monitored and their blood pressure tightly controlled. Gastroparesis may be aggravated by pregnancy hyper emesis. Autonomic neuropathy may result in erratic maternal glucose control, foetus growth retardation and foetal loss.

Ectopic adrenocortical carcinoma located in the ovary.

AIM: Ovarian corticosteroid-producing tumors are exquisitely rare. Our aim was to describe the first case observed in our practice. CASE HISTORY: A 34-year-old female was referred for Cushing's syndrome (CS) occurring in the postpartum period. Clinical examination showed severe CS with diabetes mellitus, hypertension, and a large mass in the right lower abdomen. Biochemistry demonstrated corticotropin (ACTH)-independent CS (cortisol=1900ng/mL (n=50-250), ACTH<10pg/mL (n=20-46)) with estradiol and testosterone overproduction. INVESTIGATIONS: Abdomen CT scan revealed a 14cm right ovarian mass and small adrenal glands. Surgical exploration found the ovarian tumor with hemoperitoneum and enlarged lymph nodes. Histological study confirmed adrenocortical tumor located in the ovary with a Weiss score >5, associated with peritoneal and lymph node metastases. Immunohistochemical staining was positive for inhibin-α, melan-A, and SF1, demonstrating tissue of adrenal origin. After surgery, plasma glucose level spontaneously returned to normal. However, the patient died on the second post-surgical day due to catastrophic pulmonary embolism. CONCLUSION: In this reported case, clinical, hormonal, histological, and immunohistochemical findings confirmed a cortisol and sex hormone-producing ovarian tumor with peritoneal and lymph node metastases, a very rare but important condition to recognize.

Diabetes mellitus in elderly.

Diabetes mellitus (DM) frequency is a growing problem worldwide, because of long life expectancy and life style modifications. In old age (≥60-65 years old), DM is becoming an alarming public health problem in developed and even in developing countries as for some authors one from two old persons are diabetic or prediabetic and for others 8 from 10 old persons have some dysglycemia. DM complications and co-morbidities are more frequent in old diabetics compared to their young counterparts. The most frequent are cardiovascular diseases due to old age and to precocious atherosclerosis specific to DM and the most bothersome are visual and cognitive impairments, especially Alzheimer disease and other kind of dementia. Alzheimer disease seems to share the same risk factors as DM, which means insulin resistance due to lack of physical activity and eating disorders. Visual and physical handicaps, depression, and memory troubles are a barrier to care for DM treatment. For this, old diabetics are now classified into two main categories as fit and independent old people able to take any available medication, exactly as their young or middle age counterparts, and fragile or frail persons for whom physical activity, healthy diet, and medical treatment should be individualized according to the presence or lack of cognitive impairment and other co-morbidities. In the last category, the fundamental rule is "go slowly and individualize" to avoid interaction with poly medicated elder persons and fatal iatrogenic hypoglycemias in those treated with sulfonylureas or insulin.

Pituitary Stone or Calcified Pituitary Tumor? Three Cases and Literature Review.

INTRODUCTION: Pituitary stone or pituitary calculus is a scientific enigma characterized by a large calcification in the pituitary sella. It can be discovered incidentally or in a patient with endocrine and/or neurological problems. Its mechanism is not understood. In this article, we described three patients harboring a large pituitary calcification. CASE PRESENTATION: The first case was observed in a 27-year-old woman who consulted for secondary amenorrhea. The second case concerned a woman who consulted for infertility, and the third one was observed in an 11-year and nine-month-old girl who was sent to our department for short stature. Clinical examination was normal in both adults. The pediatric case had dwarfism with lack of pubertal development. Hormonal assessment showed hyperprolactinemia in both women and thyrotroph and somatotroph deficits in the child. Radiologic exploration discovered pituitary calcifications measuring 10, 11, and 45 mm without any cystic or solid mass. CONCLUSIONS: Radiological findings pleaded for a pituitary stone, but calcified adenomas in women, and calcified craniopharyngioma in the pediatric case could not be excluded, as our three patients were not operated on.

Feminizing adrenocortical tumors: Literature review.

Feminizing adrenal tumors (FAT) are extremely rare tumors prevailing in males. Clinical manifestations are gynecomastia and/or other hypogonadism features in adults. They are rarer in pediatric population and their main manifestation is peripheral sexual precocity. In women genital bleeding, uterus hypertrophy, high blood pressure and/or abdomen mass may be the only manifestations. On the biological point, estrogen overproduction with or without increase in other adrenal hormones are the main abnormalities. Radiological examination usually shows the tumor, describes its limits and its eventual metastases. Adrenal and endocrine origins are confirmed by biochemical assessments and histology, but that one is unable to distinguish between benign and malignant tumors, except if metastases are already present. Immunostaining using anti-aromatase antibodies is the only tool that distinguishes FAT from other adrenocortical tumors. Abdominal surgery is the best and the first line treatment. For large tumors (≥10 cm), an open access is preferred to coeliosurgery, but for the small ones, or when the surgeon is experienced, endoscopic surgery seems to give excellent results. Surgery can be preceded by adrenolytic agents such as ortho paraprime dichloro diphenyl dichloroethane (Mitotane), ketoconazole or by aromatase inhibitors, but till now there is not any controlled study to compare the benefit of different drugs. New anti-estrogens can be used too, but their results need to be confirmed in malignant tumors resistant to classical chemotherapy and to conventional radiotherapy. Targeted therapy can be used too, as in other adrenocortical tumors, but the results need to be confirmed.

Neurological, psychiatric, ophthalmological, and endocrine complications in giant male prolactinomas: An observational study in Algerian population.

INTRODUCTION: Prolactinomas are less frequent, but more invasive in males. Giant ones (≥4 cm) are extremely rare in literature. Their neurological, psychiatric and endocrine complications are life threatening. Our aim was to report the largest mono center series in order to analyze their frequency, their characteristics, and their complications. SUBJECTS AND METHODS: All patients had clinical examination, hormonal, ophthalmological, and radiological assessment based on computed tomography scan and cerebral magnetic resonance imaging. Positive diagnosis was based on clinical symptoms, high prolactin ± immunohistochemy study. Mixed adenomas were excluded by hormonal exploration and immunohistochemy. For those who received medical treatment only, a reduction in tumor size was considered a supplementary positive point for the diagnosis. RESULTS: Among 154 male prolactinomas seen between 1987 and 2013, we observed 44 giant tumors (28.5%). Median age = 36 years, and 38.3% were under 30. Median tumor height = 53.95 mm (40-130) and median prolactin = 15,715 ng/ml (n < 20). Solid and cystic aspect ± calcifications was observed in 25%. 42 had cavernous sinuses invasion. Other invasions were: Posterior= 65.9%, anterior= 63.6%, temporal= 15.9% and frontal = 9%. For endocrine complications: Hypogonadism = 98.4%, thyrotroph and corticotroph deficits were seen in respectively 34%, and 32%. Posterior pituitary insufficiency was observed in one case. For ophthalmological complications: Optic atrophy = 46%, Ptosis = 6.8%, diplopia/strabismus = 4.5%. Neurological complications were: Memory loss and/or unconsciousness = 18.2%, epilepsy = 15.9%, frontal syndrome = 9% and obstructive hydrocephalus = 6.8%. CONCLUSION: Giant prolactinomas account for 28% in our population. Severe neurological complications are frequent. But, obstructive hydrocephalus is rare, which argues for a slow progression.

Diabetes mellitus and Ramadan in elderly patients.

Worldwide, the proportion of people above 60 years old represents 15% of the whole population. Diabetes mellitus is more frequent in this age group, and is associated with increased risk of morbidities and premature mortality. Aged Muslim people with diabetes insist on fasting during Ramadan, for many reasons. Elderly people, especially frail patients, who fast are at increased risk for many complications such as hypoglycaemia, hyperglycaemia and metabolic decompensation including hyperosmolar coma, diabetic ketoacidosis, dehydration and thrombosis. Therefore it is important to assess functional capacity, cognition, mental health and comorbidities in elderly people with diabetes in order to evaluate the risk of fasting, individualize the therapy, and adapt care to their needs.

Gender discrimination for women with diabetes mellitus in Algeria.

BACKGROUND: Nowadays diabetes mellitus (DM) is one of the greatest global challenges. Its expansion varies from an area to another according to genetic, traditions, socio-economic conditions, and stress. In Algeria, as in other emerging countries undergoing an epidemiological transition, noncommunicable diseases are sharply increasing. After high blood pressure, DM is now the second metabolic disease. But are women more concerned by DM since obesity frequency is higher in females? Can we assert that there is a sort of sex discrimination for DM complications? MATERIALS AND METHODS: To answer these questions we took into account published documents carried in Algerian population. But, as those were very scarce, we also considered newspapers articles, some documents published by health minister department, posters and oral communications of the Algerian Society of Endocrinology and Diabetology, and our clinical experience. We also have done a small survey to get our patients' opinions. RESULTS AND CONCLUSION: At the first sight, it seems gender discrimination between men and women cannot exist since most epidemiological studies showed that both sexes are broadly and equally affected by DM, except for old aged females who are the most affected. When we reconsidered the problem, and when we compared past results to those obtained after the terrorism period, many studies showed a sort of gender difference. Apart from gestational DM, which is increasing sharply, some complications and death related to DM are prevailing in women. Coronary diseases and cerebral vascular accidents are more frequent in women too, especially the young ones and those suffering from DM. These complications are probably due to the recent and rapid modification in women's lifestyle with a strong reduction in physical activity, eating disorders, hormonal contraception, and high sensitivity to perceived stress secondary to the near past stressing life and/or to numerous responsibilities taken by women in the modern society.

General seizures revealing macro-adenomas secreting prolactin or prolactin and growth hormone in men.

BACKGROUND: Epilepsy is a heterogeneous condition with numerous etiologies. Pituitary tumors are rarely responsible for generalized convulsions except when they are very large. Apart from anecdotic cases, only one study concerning epilepsy frequency in male macroprolactinomas is available in Medline. Our aim was to analyze epilepsy frequency and conditions under which seizures appear and disappear in men harboring macroprolactinomas or somatolactotroph adenomas. MATERIALS AND METHODS: We retrospectively analyzed 90 men with macro-adenomas (>1 cm) secreting prolactin (PRL) (n = 82) or both PRL and growth hormone (n = 8) to look for generalized seizures. We took into account familial and personal medical history, clinical examination, routine and hormonal analyzes, and radiological assessment based on cerebral magnetic resonance imaging. RESULTS: Between 1992 and 2012, we collected eight cases (8.9%): Seven were hospitalized for recent generalized seizures; one had epilepsy after conventional radiotherapy given in 1992 because of neurosurgery failure and resistance to bromocriptine. Their median age was 33.75 years (22-58), median PRL was 9,198 ng/ml and median tumor height was 74 mm (41-110). The temporal lobe was invaded in six cases. After tumor reduction, epilepsy disappeared and never relapsed after a follow-up varying between 1 and 20 years. CONCLUSION: Epilepsy, which is a life-threatening condition, can be the first presentation in men with prolactinomas or somatolactotroph adenomas, especially those involving the supra sellar area, and the brain. Convulsions can also appear after radiotherapy. That one should be avoided, if possible, before tumor reduction by surgery or medical treatment.

Diabetic retinopathy in acromegaly.

INTRODUCTION: Although growth hormone (GH) has been implicated in the pathogenesis of diabetic retinopathy (DR), DR is deemed to be rare in patients with GH excess. Our aim was to study its prevalence in subjects with acromegaly suffering from diabetes mellitus (DM), to analyze its characteristics, and to look for predictive factors such as age at diagnosis, GH concentration and duration, DM duration, DM control, and family background. MATERIALS AND METHODS: Forty patients with acromegaly and DM (21 males, 19 females), median age = 50 years, underwent a systematic ophthalmological examination with dilated funduscopy to seek diabetic retinopathy. RESULTS: Among this population, 05 (12.5%) had DR. It was at an early stage or background retinopathy in 3 cases and at a more advanced stage or proliferative retinopathy in 2 cases. We did not find any correlation with age at diagnosis, GH levels and duration, DM duration and family history of DM, but poor glycemic control seems to play a role although statistical analysis showed borderline significance. CONCLUSION: From this study, we conclude that prevalence of DR in patients with acromegaly is 12.5%, and it is slight or moderate. Among studied factors, only poor glycemic control seems to be implicated in its development.

Baraitser and Winter syndrome with growth hormone deficiency.

Baraitser-Winter syndrome (BWS), first reported in 1988, is apparently due to genetic abnormalities that are still not well-defined, although many gene abnormalities are already discovered and de novo missense changes in the cytoplasmic actin-encoding genes (called ACTB and ACTG1) have been recently discovered. The syndrome combines facial and cerebral malformations. Facial malformations totally or partially present in the same patient are: Iris coloboma, bilateral ptosis, hypertelorism, broad nasal bridge, and prominent epicanthic folds. The various brain malformations are probably responsible for growth and mental retardation. To the best of our knowledge, the syndrome is very rare as few cases have been reported so far. Our aim was to describe a child with a phenotype that looks like BWS with proved partial growth hormone (GH) deficiency which was not reported before. A girl aged 7-year-old of consanguineous parents was referred for short stature and mental retardation. Clinical examination showed dwarfism and a delay in her mental development. Other clinical features included: Strabismus, epicanthic folds, broad nasal bridge, and brain anomalies such as lissencephaly, bilateral hygroma, and cerebral atrophy. Hormonal assessment showed partial GH deficiency without other endocrine disorders. Our case looks exactly like BWS. However, apart from facial and cerebral abnormalities, there is a partial GH deficiency which can explain the harmonious short stature. This case seems worth to be reported as it adds GH deficiency to the very rare syndrome.

Suppurative meningitis: A life-threatening complication in male macroprolactinomas.

BACKGROUND: Suppurative meningitis (SM) or bacterial meningitis is a life-threatening condition, which is exceptionally due to pituitary tumors (PT). Our aim was to analyze its frequency among male macroprolactinomas (MPRL) deemed to be aggressive, to report the cases we observed in our practice and describe the circumstances under which SM appeared. MATERIALS AND METHODS: We retrospectively analyzed 82 male MPRL in order to look for a history of well proved SM and the circumstances under which SM appeared. We also took into account the possibility of SM relapsing. RESULTS: Four out of 82 male MPRL had SM = 4.87%. Three consulted for SM symptoms. SM was confirmed in Infectious Diseases department, but only one had rhinorrhea. Hormonal assessment and cerebral magnetic resonance imaging pleaded for aggressive prolactinomas. After antibiotics, SM was sterilized. Then, MPRL were treated with bromocriptine, which normalized prolactin and reduced PT. SM never relapsed. The 4(th) case was hospitalized for a large multidirectional prolactinoma invading and/or arising from the skull base. He was operated on 3 times and then he was given Bromocriptine. After 3 months, he had rhinorrhea and then SM which was successfully treated by antibiotics. SM never relapsed after tumor reduction. CONCLUSION: SM was demonstrated in 4.87%. SM has revealed MPRL in 3 cases and appeared after bromocriptine intake in the 4(th) one. Endocrinologists should be aware of this severe condition, which can be avoided by repairing as soon as possible the bony defect secondary to aggressive tumors, unless it is clogged by fibrosis: What probably happened in our cases.

Diabetes mellitus and Ramadan in Algeria.

Ramadan, one of the five pillars of Islam, is a holy month in Algeria where diabetes mellitus (DM) is more frequent in urban areas with a frequency which varies from 8 to 16%. DM complications are broadly as frequent as in developed countries, except for neuropathy which seems more frequent. Despite contraindications which are regularly explained to our patients and despite the flexible side of Islam toward chronic diseases, most Algerian people with DM insist on fasting. Not fasting is considered a sin and shameful. There are also other reasons put forward by diabetic persons, such as very strong religious faith, habit of fasting together with the whole family since an early age, solidarity with the family, friends, and neighbors, and finally and probably because of the desire to appear "normal" and share a festive and a spiritual atmosphere of Ramadan. As in other Muslim countries, severe hypoglycemia the main motive of hospitalizations during the holy month, ketoacidosis, dehydration, orthostatic hypotension and thrombosis are some of the complications which Algerian people with DM are exposed to when fasting.

Severe gynecomastia due to anti androgens intake: A case report and literature review.

Gynecomastia is the most bothersome side effect in men taking antiandrogens. It is exceptionally severe and distressing physically and mentally as in the reported case. A man, aged 63, with a history of a well-treated macroprolactinoma, was referred in 2004 for gynecomastia that appeared after treatment by microsurgery, radiotherapy and flutamide for a lesion suspected to be prostate cancer. Clinical examination was normal except for huge enlargement of the breasts. Mammography and breasts MRI did not show any tumor. There was not any metastasis of the supposed prostate cancer and prostatic acid phosphates were within normal ranges. Hormonal exploration showed subclinical hypogonadism [testosterone: 7.4 ng/ml (n: 3-9), FSH: 14.9 mu/ml (n: 0.7-11) and LH: 9.7 mu/ml (n: 0.8-7.6)]. Testes ultrasounds were normal. Radiological and hormonal adrenal explorations were normal [Cortisol: 76 ng/ml (n: 50-250), DHEA-S: 59 µg/ml (n: 50-560), E2:40.2 pg/ml (n < 50)]. Body scan was normal too. The discussed etiologies were post radiation subclinical hypogonadism, and treatment with anti androgens. After flutamide withdraw, there was not any sign of prostate cancer recurrence, and gynecomastia decreased significantly, but did not disappear probably because of fibrosis.