Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Carbohydrate-lipid profile and use of metformin with micronized fenofibrate in reducing metabolic consequences of craniopharyngioma treatment in children: single institution experience.

AIM: To evaluate auxology and metabolic disturbances in children with craniopharyngioma, and to present observational results of treatment of metabolic sequels with metformin and micronized fenofibrate. METHODS: The studied group comprised 22 children [median age at diagnosis 10.5 (0.17-16.75) years; median follow-up 5.1 years]. Assessment included height standard deviations (SDS), body mass index (BMI) SDS, concentrations of lipids, glucose and insulin (fasting or oral glucose tolerance test) and homeostatic model assessment of insulin resistance (HOMA-IR) index. Ten adolescents with hyperinsulinemia and dyslipidemia received therapy with metformin (500-1500 mg/daily) and micronized fenofibrate (160 mg/daily). RESULTS: At diagnosis, median hSDS was -1.66 (range: -4.08; +0.1). Nine (40.9%) children were growth hormone-treated. There was gradual increase of BMI SDS, 18 (81.8%) patients being overweight at the final assessment. Dyslipidaemia was found in 19 patients (86.4%), hyperinsulinaemia in 11 patients (50%) and elevated HOMA-IR in 15 patients (68.2%). Decrease of triglycerides [median 263.5 (171-362) mg/dL vs. 154 (102-183) mg/dL] and HOMA-IR [8.64 (5.08-12.65) vs. 4.68 (0.7-7.9)] was significant in the group treated with metformin and fenofibrate for 6 months. CONCLUSIONS: Significant auxologic changes and metabolic abnormalities were found in children treated for craniopharyngioma. The use of metformin and fenofibrate seemed to attenuate these disturbances in a short-term observation.

Nijmegen breakage syndrome (NBS).

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.

High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study.

CONTEXT: Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited. OBJECTIVE: Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation. STUDY DESIGN AND PATIENTS: The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed. RESULTS: None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus. CONCLUSIONS: Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.

Practical approach to childhood craniopharyngioma: a role of an endocrinologist and a general paediatrician.

OBJECTIVES: The objectives of this study are to evaluate co-morbidities in patients with craniopharyngioma and to elaborate an interdisciplinary protocol of the follow-up. PATIENTS AND METHODS: The group comprised 15 children (median age at the diagnosis, 10.1; mean follow-up period, 4 years). All patients had surgical resection of the tumour: gross total in seven, subtotal or partial removal in eight cases. Surgery was followed by radiotherapy in ten cases for tumour residue or progression. Sexual development and auxology were evaluated at diagnosis and during follow-up. Hormones were determined by chemiluminescent immunometric assays. Antidiuretic hormone dysfunction was diagnosed on the grounds of clinical symptoms, water-electrolyte balance, urine specific gravity, and serum osmolality. Metabolic control was monitored by levels of glucose, insulin, lipids, and transaminases; insulin resistance was expressed by homeostatic model assessment (HOMA) index. RESULTS: At diagnosis, median height standard deviation score (hSDS) was -1.6 (five children being short-statured). Median change hSDS for the whole follow-up was 1.2 (four children decelerating growth). Diabetes insipidus was diagnosed in eight (within 0-1.8 years of the follow-up), hypocorticolism in eight, and hypothyroidism in 12 subjects (within 0-3.75 years for both endocrinopathies). Four patients required sex hormone replacement therapy. At diagnosis, five children were overweight; during follow-up, only four children sustained normal body mass index. Hypertransaminasaemia was found in three, dyslipidaemia in 11, and hyperinsulinaemia in seven patients (with elevated HOMA in four cases). CONCLUSIONS: On the grounds of these observations, the management of craniopharyngioma in our institution includes repeated hormonal and metabolic assays in chosen time intervals. Early detection of co-morbidities and their management involves interdisciplinary team.

[Causes of precocious puberty in children referred for evaluation in hospital conditions]. / Przyczyny przedwczesnego dojrzewania dzieci kierowanych do dianostyki w warunkach szpitalnych.

INTRODUCTION: Symptoms of precocious puberty (PP) in children always arouse anxiety in their parents. Many children with PP are being hospitalized for the detailed diagnostic work-up. The aim of our study was to analyze the frequency of the variants of PP in children referred to our department. MATERIAL: Retrospective analysis of 119 children (103 girls and 16 boys) referred for hospitalization in the years 2003-2005 due to signs of precocious puberty was performed. RESULTS: Premature thelarche, benign variant of puberty, was diagnosed in 62 (53%) girls, in the mean age of 3.39 (+/- 2.33) years. Their mean height was within 0.7 +/- 1.1 SD. Premature pubarche was diagnosed 30 (25%) children--22 girls and 8 boys in the mean age was 7.24 (+/- 0.81) years. Their mean height was 1.3 +/- 1.0 SD and was significantly higher than normal (p < 0.0001). Premature menarche was diagnosed in 8 (7%) girls in the mean age 4.81 +/-2.26 years. Mean height in this group was normal for age (0.9+/-0.8 SD). PP was diagnosed in 19 (16%) children (11 girls and 8 boys) in the mean age 5.91 +/- 1.63 years. Mean height in this group was 1.6 +/- 0.7 SD, and was significantly higher than the mean for age (p<0.0005). GnRH-dependent type was present in 15 children, diagnosed as idiopathic in 9 girls and 1 boy. In 5 children (4 boys and 1 girl) pathology of central nervous system was found. In 4 children GnRH-independent precocious puberty was diagnosed--in 3 caused by congenital adrenal hyperplasia and in 1 boy by tumour of testis (leydigioma). CONCLUSIONS: Girls with precocious thelarche without growth acceleration present the benign variant of puberty and need clinical follow up only. Boys with clinical signs of precocious puberty should be carefully evaluated to rule out the organic cause.

[Diagnostic difficulties in diagnosis of splenic abscesses]. / Trudnosci diagnostyczne w rozpoznawaniu. ropni sledziony.

We report an 18-year old patient with hypochromic anaemia and subfebriles states and long-persisting despite symptomatic treatment. On admission he presented body proportions similar to Marfan syndrome. Hypochromic anaemia and positive inflammatory markers were present along with negative results of serologic and microbiological assays. Hormonal parameters, as well as karyotype were normal. Among several imagining procedures, ultrasound and CT of the abdomen revealed areas in the spleen suggestive of proliferative disease or abscesses. Bone marrow examination was normal. Because of high probability of the disease limited to the spleen and deteriorating clinical state of the patient, splenectomy was performed. After the operation significant improvement of the health state of the patient was observed. Histopathological evaluation showed splenic abscesses. However, anamnesis and accessory examinations did not reveal their etiology. This report is an example of possible difficulties in diagnosing splenic abscesses, as well as supports grounds for surgical intervention in chosen cases.

[Ultrasound examination of the scrotum in boys]. / Badanie sonograficzne worka mosznowego u chlopców.

BACKGROUND: Ultrasound examination is applied in the objective evaluation of size of scrotal structures as well as in diagnosing focal and inflammatory lesions in testes and epididymis. AIM: The aim of our study is to point out the necessity and significance of the ultrasound in diagnostics of abnormalities within the scrotum in boys. MATERIAL AND METHODS: The examination included 180 boys, aged 2-17 years, referred because of gynecomastia (70), cryptorchism (45), precocious puberty (11), palpable thickenings of the spermatic cord (30) and asymmetry of testicular size (24). Ultrasound examination was carried out with Acuson 128 XP, linear transducer 7.5 MHz, along with color flow Doppler (and/or Sequoia, linear transducer 8-15 MHz). RESULTS: Testes in the inguinal canals at different levels were visualised in all boys with unilateral or bilateral cryptorchism. Varicocele were seen in 19 boys with gynecomastia, epididymal cysts in 10, microlithiasis in 3 cases. Testicular volume in boys with precocious puberty exceeded 2 SD, additionally there was microlithiasis in one patient, in 2 patients varicocele and in one boy tumor was found (Leydig's cell tumor). Varices were left-sided in 95% boys with varicocele, in 5% they were bilateral at different stage. Additionally in one patient hygroma of the spermatic cord was found. Asymmetry of testicular size was caused by hydrocele in 16 patients and varicocele in 8 cases. CONCLUSIONS: Ultrasound is supplementary to the physical examination of testes, and in many cases it enables to reveal lesions inaccessible in the clinical examination. Considering its non-invasive character and high-resolution, ultrasound is a useful imaging method of the scrotal structure in children.

[GnRH-dependent precocious puberty in a boy with Leydig-cell tumor]. / Przedwczesne dojrzewanie GnRH-zalezne u chlopca z guzem z komórek Leydiga.

GnRH-dependent precocious puberty in a boy with Leydig-cell tumor is presented. Precocious activation of the hypothalamo-pituitary axis was caused by long-term exposition to sex-steroids. Long-acting LHRH-analog treatment suppressed the process of precocious puberty.