Maria A. Kalina

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.Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów.Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest przyczyną nawracających infekcji, znaczna predyspozycja do rozwoju nowotworów złośliwych (zwłaszcza układu chłonnego), a także zwiększona wrażliwość na promieniowanie jonizujące. Wyniki badań laboratoryjnych wykazują: (1) spontaniczną łamliwość chromosomów w limfocytach T krwi obwodowej, z preferencją do rearanżacji chromosomów 7 i 14, (2) nadwrażliwość na promieniowanie jonizujące lub radiomimetyki, co można wykazać metodami in vitro, (3) radiooporność syntezy DNA, (4) hipomorficzne mutacje na obu allelach genu NBN, oraz (5) brak w komórkach pełnej cząsteczki białka, nibryny. Małogłowie i niedobór odporności występują także w zespole niedoboru ligazy IV (LIG4) oraz w zespole niedoboru NHEJ1. Rodzice powinni otrzymać poradę genetyczną ze względu na wysokie ryzyko (25%) powtórzenia się choroby u kolejnego potomstwa. Możliwe jest zaproponowanie molekularnej diagnostyki prenatalnej jeżeli znane są obie mutacje będące przyczyną choroby. Nie ma możliwości zaproponowania specyficznej terapii, ale przeszczep szpiku może być alternatywą dla niektórych pacjentów. Generalnie prognoza nie jest pomyślna z uwagi na wysokie ryzyko rozwoju nowotworu.

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.

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

Abstract 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.

Prospective assessment of continuous subcutaneous insulin infusion therapy in young children with type 1 diabetes

The study assessed 3.5-year treatment with continuous subcutaneous insulin infusion (CSII) in well-controlled children with duration of type 1 diabetes mellitus longer than 1 year. Following groups were observed: the CSII group-40 children and the multiple injections (MDI) group-36 patients (age-matched, the mean of 6.5+/-2.1 and 7.1+/-1.8 years, respectively). At the onset of the follow-up both groups were comparable in age, HbA1c, daily insulin requirement (DIR), body weight, height and BMI. They were followed from the start, and every 6 months in relation to DIR, HbA1c, acute complications (DKA, hypoglycaemia) and physical development. Mean HbA1c and DIR for the whole study period were lower in the CSII versus MDI group (6.90+/-0.54 vs 7.22%+/-0.16 and 0.75+/-0.16 vs 0.88+/-0.13 U/kg/d; p<0.05). HbA1c was lower in the CSII versus MDI group in months 6 and 42 (6.95 vs 7.29%, and 6.91 vs 7.43%, respectively; p<0.05). DIR was significantly lower at most intervals in the CSII group. No significant differences regarding number of complications and anthropometry were found. CSII allows for near-normal metabolic control and lower insulin requirement comparing to the MDI method. CSII is safe treatment, assuring harmonious childs development.

Do children with Adams-Oliver syndrome require endocrine follow-up? New information on the phenotype and management

Kalina MA, Kalina‐Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marszał E, Małecka‐Tendera E. Do children with Adams‐Oliver syndrome require endocrine follow‐up? New information on the phenotype and management.

Treatment of severe primary IGF-1 deficiency using rhIGF-1 preparation – first three years of Polish experience

INTRODUCTION The objective of this study was to analyse the effects of the first three years of treatment with recombinant human insulinlike growth factor 1 (rhIGF-1) in patients from the Polish population. MATERIAL AND METHODS Twenty-seven children (22 boys and five girls) aged 2.8 to 16.0 years old were qualified for treatment with rhIGF-1 (mecasermin) in different treatment centres, according to Polish criteria: body height below -3.0 SD and IGF-1 concentration below percentile 2.5 with normal growth hormone (GH) levels. Mecasermin initial dose was 40 μg/kg bw twice a day and was subsequently increased to an average of 100 μg/kg bw twice a day. Body height, height velocity, weight, body mass index (BMI), and adverse events were measured. RESULTS Mecasermin treatment resulted in a statistically significant increase in body height (1.45 ± 1.06 SD; p < 0.01) and height velocity in comparison with pre-treatment values. The biggest change in height velocity happened during the first year and diminished during subsequent years. Body weight and BMI also increased significantly after treatment (1.16 ± 0.76 SD and 0.86 ± 0.75 SD, respectively; p < 0.01). Eight patients reported adverse events. These were mild and temporary and did not require treatment modification except in two patients. CONCLUSIONS Treatment with rhIGF-1 was effective and safe in Polish patients with primary IGF-1 deficiency. It had a clear beneficial effect on the height of the patients and significantly accelerated the height velocity, particularly in the first year of treatment.

Zespół Silvera-Rusella. Część II.

Niektóre cechy zespołu Silvera-Russella (SRS) mogą być wspólne z innymi jednostkami odznaczającymi się wewnątrzmacicznym ograniczeniem wzrastania, stąd kliniczne rozpoznanie tego zespołu jest często niejednoznaczne. Liczne skale punktowe, stale modyfikowane, oparte są na pomiarach antropometrycznych, cechach dysmorfii i na występowaniu objawów chorobowych związanych m.in. z zaburzeniami żołądkowo-jelitowymi i nieprawidłowym wzrastaniem. Na podstawie obrazu klinicznego pacjenci są kwalifikowani do badań genetycznych. Obejmują one analizę metylacji loci 11p15 jak również zaburzeń metylacji/piętnowania wielu loci (ang. multilocus methylation/imprinting defects; MLMD/MLID). W diagnostyce SRS wykorzystywane są także techniki analizy jednorodzicielskiej matczynej disomii chromosomu 7 (UPD(7)mat) i metody cytogenetyki molekularnej w przypadku podejrzenia rearanżacji submikroskopowych. Ryzyko powtórzenia się SRS w rodzinie jest małe; znane rzadkie przypadki rodzinne uwarunkowane są dodatkowymi mechanizmami genetycznymi. Dzieci z SRS powinny pozostawać pod wielospecjalistyczną opieką. Słaby przyrost masy ciała czy refluks żołądkowo-przełykowy wymagają dokładnej oceny przez gastroenterologa i dietetyka pod kątem zapotrzebowania kalorycznego i składu pokarmów. Wzrost i dojrzewanie powinny być monitorowane przez endokrynologa. Dostępne jest również leczenie rekombinowanym lub biopodobnym hormonem wzrostu. Natomiast rozwój psychoruchowy dzieci z SRS powinien być nadzorowany przez zespół składający się z logopedy, rehabilitanta, psychologa i neurologa. Nadal potrzebne są badania w grupach z potwierdzonym genetycznie SRS w celu długofalowej oceny rozwoju i możliwych następstw metabolicznych, w szczególności zaburzeń gospodarki węglowodanowej w tej grupie pacjentów.

Auxologic parameters and response to 2-year therapy with recombinant human growth hormone in growth hormone deficient children with an ectopic posterior pituitary.

BACKGROUNDStructural defects of the hypothalamic-pituitary area in MRI are suggested as being a more accurate marker of growth hormone deficiency (GHD) than laboratory assays.OBJECTIVETo compare auxological characteristics in GHD children with normal pituitary (NP) function and with ectopic posterior pituitary (EPP), prior to therapy with recombinant human growth hormone (rhGH), extending the follow-up to two years following treatment.DESIGNEighty-six (86) GHD patients were divided into two groups depending on the pituitary MRI: the EPP (23 children, 3.2–16.8 years old) and the NP group (63 children, 3.3–14.8 years old). Height deficits in the population (hSD) and parents (hSD-mpSD) and the change of hSD and bone/chronological age ratio were assessed before and after 12 and 24 months of rhGH therapy.RESULTSHeight deficits before treatment were significantly greater in EPP compared to NP [median −4.07 (−7.06, −2.75) −3.15 (−4.9, −2.35) for hSD, and −3.65 (−7.06, −1.21) vs −1.83 (−4.31, −0.28) for hSD-mpSD; p<0.05]. Bone age was significantly delayed in the EPP group [0.62 (0.27, 0.92) vs 0.75 (0.21, 0.71); p<0.05]; differences remained significant during follow-up. After 12 months of rhGH therapy, EPP showed significantly greater catch-up growth compared to NP [ΔhSD=1.2 (0.42, 2.69) vs 0.74 (0.05, 1.48); p<0.05]. In the 2nd year, height velocity slowed down and was comparable in the two groups. At the conclusion of the study, hSD was similar in both groups, but hSD-mpSD was more deviated in EPP [−1.79 (−3.71, −1.21) vs −1.1 (0.98, −0.07); p<0.05].CONCLUSIONSThe study showed relevant auxologic differences between EPP and NP children, as well as beneficial effects of rhGH therapy in both groups.