Evaluation of catch-up growth in severe pediatric Hashimoto's hypothyroidism.

BACKGROUND: We aimed to evaluate catch-up growth in children with severe Hashimoto's hypothyroidism (HH) after thyroid hormone replacement therapy (HRT). METHODS: A multicenter retrospective study was conducted including children referred for growth slowdown that led to the diagnosis of HH between 1998 and 2017. RESULTS: A total of 29 patients were included, with a median age of 9.7 years (13-172 months). Median height at diagnosis was -2.7 [-4.6; -0.1] standard deviation score (SDS), with a height loss of 2.5 [0.7; 5.4] SDS compared to height before growth deflection (p<0.0001). At diagnosis, the median TSH level was 819.5 mIU/L [100; 1844], the median FT4 level was 0 pmol/L [undetectable; 5.4], and the median anti-thyroperoxidase antibody level was 1601 UI/L [47; 25,500]. In the 20 patients treated only with HRT, there were significant differences between height at diagnosis and height at 1 year (n = 19, p<0.0001), 2 years (n = 13, p = 0.0005), 3 years (n = 9, p = 0.0039), 4 years (n = 10, p = 0.0078), and 5 years (n = 10, p = 0.0018) of treatment but not in the case of final height (n = 6, p = 0.0625). Median final height was -1.4 [-2.7; 1,5] SDS (n = 6), with a significant difference between height loss at diagnosis and total catch-up growth (p = 0.003). The other nine patients were also given growth hormone (GH). They were smaller at diagnosis (p = 0.01); however, there was no difference in final height between those two groups (p = 0.68). CONCLUSION: Severe HH can lead to a major height deficit, and catch-up growth seems to be insufficient after treatment with HRT alone. In the most severe cases, administration of GH may enhance this catch-up.

Do children and adolescents with type 1 diabetes suffer from a lack of resources in France? Results from a benchmark study in the New Aquitaine region.

BACKGROUND: A benchmark study was conducted in the southwest of France, in the New Aquitaine region, to investigate metabolic outcomes and availability of resources in pediatric diabetes units. We assessed whether the level of care was in accordance with the International Society for Pediatric and Adolescent Diabetes recommendations. METHODS: Demographic and clinical data were collected, as were all HbA1c tests for the 2017 calendar year. Pediatricians specialized in diabetes care were invited to complete an online survey concerning means allocated to the management of type 1 diabetes in their centers. RESULTS: Sixteen centers provided data for 1277 patients and 3873 clinical visits. A total of 1115 children suffering from diabetes for more than 1 year were studied. Median HbA1c was 8% (7.4-8.6) for the whole region. Only 29.2% of children had good metabolic control in accordance with the <7.5% target. We identified slight but significant variation in glycemic control among centers (P=0.029). The use of an insulin pump varied greatly among centers but did not explain HbA1c differences. We did not identify a correlation between medical or paramedical time dedicated to the follow-up of diabetic patients and the mean HbA1c of each center. For 100 diabetic patients, follow-up was provided by 0.42 physicians (0.23-1.50), 0.15 nurses (0-0.56), 0.12 dietitians (0-0.48), and 0.07 psychologists (0-0.30). CONCLUSION: This study demonstrates a lack of human resources allocated to the management of type 1 diabetes in the region that is far below international recommendations. The proportion of children achieving the international glycemic target is low. There is a clear need to improve glycemic control in children, which will only be possible with improved professional practices, encouraged by benchmark studies, and by increasing the size of our multidisciplinary teams.

A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense activating mutations of the calcium-sensing receptor (CaSR) gene, a G-protein-coupled receptor playing key roles in mineral ion metabolism. We now describe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame deletion of 181 amino acids within its carboxylterminal-tail from S895 to V1075. Interestingly, the affected grandfather is homozygous for the deletion but no more severely affected than heterozygous affected individuals. Functional properties of mutant and wild-type (WT) CaSRs were studied in transiently transfected, fura-2-loaded human embryonic kidney (HEK293) cells. The mutant receptor exhibited a gain-of-function, but there was no difference between cells transfected with mutant complementary DNA alone or cotransfected with mutant and WT complementary DNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. Therefore, this activating deletion may exert a dominant positive effect on the WT CaSR. The mutant receptor's cell surface expression was greater than that of the WT CaSR, potentially contributing to its gain-of-function. This novel mutation in the CaSR gene provides the first known examples of a large naturally occurring deletion within a G-protein-coupled receptor's carboxylterminal-tail and of a homozygous, affected individual with ADH.

Relative contributions of inferior petrosal sinus sampling and pituitary imaging in the investigation of children and adolescents with ACTH-dependent Cushing's syndrome.

Selective transsphenoidal microadenomectomy is the first line treatment of childhood Cushing's disease, with accurate preoperative localization of the corticotroph adenoma an important step in its investigation. Inferior petrosal sinus sampling (IPSS) for ACTH after CRH stimulation is a recognized investigation in adults, but there are few data in the pediatric age range. We report the relative contributions of IPSS and pituitary imaging in 11 patients, aged 10.7-18.8 yr, presenting with Cushing's disease. All underwent transsphenoidal surgery (TSS). IPSS was performed without complication. Sampling was from the inferior petrosal sinuses in 7 patients and the high jugular veins in 4 (patients 2, 4, 5, and 10). The central to peripheral ACTH (IPS/P) ratios were more than 2 (2.5-157.2) in 10 of 11 patients, confirming central ACTH secretion. In 3 patients with high jugular sampling, IPS/P ratio ranged from 2.5-21.1. In the fourth patient with high jugular sampling (IPS/P ratio, 0.95), a central adenoma was identified surgically, and the patient was cured after TSS. The interpetrosal sinus ACTH gradient (IPSG) was more than 1.4 (2.1-20.8) in 10 patients, indicating lateralization of ACTH secretion to the right side in 6 patients and to the left in 4. IPSG ratios were 2.1-8.5 in 3 patients with high jugular sampling. Pituitary imaging (computed tomography and or magnetic resonance imaging) was reported to identify an adenoma in 5 of 11 patients. At operation a tumor was visualized by the same surgeon in all 11 cases. In 9 patients with lateralization on IPSS, the correct side of the tumor was confirmed at surgery. In a 10th patient with a negative IPSG, a central tumor was present. Thus, IPSS gave a 91% prediction of correct tumor localization. In only 1 of 5 patients with an adenoma reported on pituitary imaging was this localization confirmed at surgery, a prediction rate of only 9%. After TSS, 8 patients were cured, 1 was in remission, and 2 required pituitary irradiation. In 73% of patients undergoing IPSS, localization of the adenoma was followed by surgical cure or remission. Pituitary scanning was therefore relatively unhelpful in localizing the adenoma. In experienced hands, however, IPSS was feasible in this age group, safe, and strongly predictive of the site of the adenoma, leading to a high rate of successful surgical outcome.

Activating mutations of the calcium-sensing receptor: management of hypocalcemia.

Activating mutations of the calcium-sensing receptor (CaR) can cause isolated hypoparathyroidism. Treatment of hypocalcemia in these patients remains to be optimized, because the use of 1-hydroxylated vitamin D3 derivatives can cause hypercalciuria and nephrocalcinosis. We identified activating CaR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism. The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia; serum Ca was 1.97 +/- 0.08, 1.82 +/- 0.14, and 1.54 +/- 0.22 mmol/liter, respectively, in asymptomatic (n = 7), mildly symptomatic (n = 8), and severely symptomatic patients (n = 6). Hypocalcemia segregated with the CaR mutation, but no phenotype-genotype relationships were identified. Fourteen patients received regular 1-hydroxylated vitamin D3 treatment (mean duration, 7.2 +/- 4.9 yr). Nine had hypercalciuric episodes, which were associated with nephrocalcinosis in eight cases. Serum Ca during treatment predicted hypercalciuria and nephrocalcinosis poorly, because either or both of the latter could develop in hypocalcemic patients. Thus, mutational analysis of the CaR gene should be considered early in the work-up of isolated hypoparathyroidism. Treatment options should be weighed carefully in patients with serum Ca below 1.95 mmol/liter. The risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary Ca excretion.

Insulin secretion and sensitivity in children on cyclic total parenteral nutrition.

BACKGROUND: Some children receiving total parenteral nutrition (TPN) have abnormal glucose tolerance. METHODS: Insulin secretion and sensitivity were studied in 12 patients, aged 5.7 to 19.4 years, receiving cyclic nocturnal TPN. Insulin secretion was measured during an IV glucose tolerance test (IVGTT; 0.5 g/kg) followed by a hyperglycemic clamp (plasma glucose at 10 mmol/L). Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp (insulin infusion = 1 mU/kg/min). RESULTS: Patients with normal glucose tolerance receiving TPN had an insulin response to IVGTT similar to that of normal children of the same age. Insulin levels of TPN patients were higher than those in healthy young adults during the hyperglycemic clamp. Whole body glucose disposal was greater in younger than in older children (range, 7.1 to 25.2 mg/kg/min), and this inverse correlation with age was statistically significant (p < .01). Two patients with abnormal glucose tolerance showed a decreased capacity to release insulin, whereas insulin sensitivity was unchanged in one of these two patients. Two patients treated with prednisone or octreotide had insulin levels similar to those of normal TPN children. CONCLUSIONS: The insulin response to sustained hyperglycemia was stronger in children with normal glucose tolerance on cyclic TPN. Patients with a limited capacity to release insulin, either constitutional or acquired, may not be able to produce enough insulin in these conditions and develop glucose intolerance during TPN. Insulin sensitivity was not a key factor in the alteration of glucose tolerance.

Double maternal seroconversion to cytomegalovirus and Toxoplasma gondii.

BACKGROUND: We report the first case of a double maternal seroconversion for Toxoplasma gondii (TG) and cytomegalovirus (CMV) diagnosed during pregnancy. CASE: One case is reported of a female patient referred for seroconversion in response to TG in the 27th week of gestation. A search for foetal involvement revealed signs of non-specific foetal infection without any TG-related lesions. Tests were carried out for another foeto-maternal infectious disease and maternal seroconversion in response to CMV was discovered with virus in the amniotic fluid. The foetus developed hydrocephalus and intracranial calcifications and the pregnancy was terminated at the parents' request. CMV-induced multiple organ involvement without any signs of Toxoplasma gondii-related involvement were noted in the foetus. CONCLUSIONS: This case indicates that a search should be made for another infectious disease likely to involve the foetus when non-specific signs of infection in the foetus are present, even though maternal seroconversion has been recognized.

[Treatment of neonatal thrombocytopenia]. / Traitement d'une thrombopénie néonatal.

Treatment of neonatal thrombocytopenia is dependent on its etiology and severity. The best indication for treatment with immunoglobulins is autoimmune thrombocytopenia. Platelet and blood transfusions are justified mainly in the presence of severe infection. The only indication for platelet transfusion is severe thrombocytopenia (platelet count below 30 G/L).

[Ischemic stroke caused by neuroborreliosis]. / Accident ischémique cérébral lié à une neuroborréliose.

UNLABELLED: Ischemic stroke in children is rare and its etiology is frequently unknown. CASE REPORT: We report the case of a nine-year-old boy who presented a right ischemic lenticular stroke due to neuroborreliosis, with a good outcome after antibiotic treatment. CONCLUSION: We suggest that it is important to search for neuroborreliosis in case of an ischemic stroke in children; the study of cerebral spinal fluid is a good diagnostic marker.

[The efficacy of smectite in acute infantile diarrhea, compared to a placebo and loperamide]. / Etude de l'efficacité de la smectite dans les diarrhées aiguës du nourrisson, comparativement à un placebo et au lopéramide.

Fifty-six infants (aged 2 months to two years) with moderate to severe diarrhea were entered in a comparative therapeutic trial of smectite versus placebo or loperamide. Results showed that diarrhea resolved faster under smectite than under placebo and at least as fast under smectite as under loperamide. Tolerance of smectite is excellent as a result of the lack of any effect on intestinal motility.

[24 cases of human parvovirus B19 infection in children]. / A propos de vingt-quatre observations d'infections à parvovirus humain B19 chez l'enfant.

From January 1, 1987 through December 31, 1990, twenty-four pediatric patients with human parvovirus B19 (HPV B19) infection were seen. In every case the diagnosis was established by a positive capture immunoassay for IgM antibodies against the HPV B19. Four patients had hematologic manifestations, including one case of transient bone marrow aplasia revealing hereditary spherocytosis, one case of autoimmune hemolytic anemia with beta-thalassemia, and two cases of peripheral thrombocytopenia. Eight patients had skin lesions, with a morbilliform rash in six cases, erythema nodosum in one case, and Gianotti-Crosti syndrome in one case. No patients had erythema infectiosum. Seven patients developed joint manifestations: Henoch-Schönlein purpura in two cases, arthralgia in four cases, and polyarticular disease progressing to severe rheumatoid arthritis in a thirteen-year-old girl. Unremarkable symptoms of viral disease were seen in three patients. A five-month-old infant developed severe acute myocarditis. One patient with hepatitis A had acute liver failure. This study confirms the broad spectrum of clinical manifestations of HPV B19 infection. There were a number of unusual findings, including the high rate of joint manifestations (29%) and the severe course of some hematologic and myocardial manifestations. These results raise the question of whether the HPV B19 may be involved in the genesis of chronic juvenile arthritis.

Insulin resistance and excess weight in adolescent insulin-dependent diabetic girls.

Insulin dependent diabetic adolescent girls show a tendency towards excess weight. The relationship between insulin resistance and body mass index (BMI) was investigated in 23 Type 1 adolescents aged 13-20 yr. These patients body mass indexes spanned from 19.8 to 30.5. Excess weight was evaluated using Z-scores, corrected for age with reference to french standards. 9 patients with a Z-score greater than 2 were considered as obese. Insulin sensibility was measured using the hyperinsulinaemic euglycaemic clamp (insulin infusion rate, 1 mU kg-1 min-1). The mean glucose infusion rate during the clamp was low in the diabetic girls (2.29 +/- 1.35 mg kg-1 min-1), confirming the existence of insulin resistance. However, the degree of insulin resistance was not correlated with the excess in weight (glucose infusion rate, 2.23 +/- 1.24 vs 2.33 +/- 1.46 mg kg-1 min-1 in the obese and the non-obese patients, respectively). None of the factors which influence on insulin sensitivity could explain this lack of correlation, the obese patients showing greater daily insulin doses (1.36 +/- 0.22 vs 1.22 +/- 0.25 unit kg-1 day-1) and worse metabolic control (Hba1C, 10.9 +/- 1.4 vs 10.2 +/- 2.0%). Insulin resistance was significantly correlated with free fatty acid levels during the clamp.

A rare cause of fetal ascites: A case report of Günther's disease.

Despite an arsenal of ever-improving diagnostic tools, determining the precise etiology of fetal ascites is not always possible. We report a case history where moderately-severe fetal ascites was retrospectively determined to be due to Günther's disease (congenital erythropoietic porphyria). The infant was found to carry the mutation associated with the most severe disease phenotype in which fetal hydrops has been described.

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling.

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood.

Growth abnormalities associated with adrenal disorders and their management.

Linear growth can be disturbed in paediatric adrenal disease associated with endocrine hypo- or hyperfunction. Tall stature is a feature in some patients with adrenocorticotropic hormone resistance syndromes and short stature is recognized in the IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) association. In autoimmune Addison's disease, growth is usually normal. In congenital adrenal hyperplasia, height may be compromised by advanced skeletal maturation or by suppressed growth, particularly in the neonatal period due to excess glucocorticoid treatment. In virilizing adrenal tumours, height is increased at diagnosis, but after surgical cure final height is usually in the normal range. In Cushing's disease, height was abnormally short in 50% of patients at presentation. After successful treatment, spontaneous catch-up growth was not seen. This led to a diagnosis of growth hormone (GH) deficiency in 80% of patients. With GH replacement, catch-up growth and long-term benefit occurred. Disturbance of linear growth is an important feature of many patients with adrenal disorders in childhood. Assessment of its pathogenesis and careful management are necessary to ensure optimal final adult height.

Cushing's disease in childhood: presentation, investigation, treatment and long-term outcome.

Seventeen patients with Cushing's disease (CD) were treated from 1978 to 2000. There were 11 males and 6 females aged 6.8-18.8 years (mean age 13.0 +/- 5.9 years). Presenting features were: weight gain (100%); growth failure (71%); hirsutism (53%); striae (53%); hypertension (47%). Mean age of patients with striae was 15.2 +/- 2.3 years, without striae 10.3 +/- 3.3 years. Median height SDS was -1.81 (range -0.28 to -4.17), 53% having height SDS < -1.8. The height velocity in 6 subjects was subnormal (0.9-3.8 cm/year). Median BMI SDS was 2.29 (range 1.72-5.06). Cushing's disease was confirmed by detectable serum ACTH, median 28 ng/l (range 12-99, NR <10-50) (n = 15); loss of cortisol circadian rhythm values at midnight ranging from 216 to 1,080 nmol/l (NR <50) (n = 15); lack of cortisol suppression (NV < 50 nmol/l) during low-dose dexamethasone suppression test (LDDST) (0.5 mg 6-hourly x 8) (n = 14); and >50% suppression of cortisol compared with the basal value during high-dose dexamethasone suppression test (HDDST) (2 mg 6-hourly x 8) (n = 14). A CRH test (1 microg/kg i.v.) showed an increase of cortisol from 12 to 217% (median 73.5%) (n = 16). Pituitary imaging (CT/MRI) showed an image consistent with microadenoma in 6/17 patients, but there was concordance between pituitary imaging and surgical findings in 1/11 patients (9%). Inferior petrosal sinus sampling (IPSS) for ACTH after CRH was performed in 11 subjects (age 10.7-18.8 years). Central to peripheral ACTH ratios were >2 (2.5-157.2) in 10/11 patients. The inter-petrosal sinus ACTH gradient was >1.4 in 10 patients (2.1-20.8), indicating lateralization of ACTH secretion. In 10 patients (91%), the side of the tumour on IPSS was predictive of findings at surgery. Therapy consisted of transsphenoidal microadenomectomy (TSS) in 16 patients and bilateral adrenalectomy (1978) in 1. Following TSS alone, 7 patients were cured (cortisol <50 nmol/l) and 2 were in remission (cortisol <300 nmol/l), i.e. 56%. Seven had persisting hypercortisolaemia and underwent pituitary irradiation (4,500 cGy). Therapeutic outcome for a median of 8 years (0.5-24 years) resulted in cure of CD in 14/17 patients (82%) and remission in 1. Linear growth after TSS +/- pituitary irradiation in 10 subjects showed no short-term catch-up growth, with peak growth hormone (GH) 0.5-20.9 mU/l to insulin tolerance test (ITT)/glucagon. Eight patients were treated with human growth hormone (hGH) (14 U/m(2)/week) combined in 3 with GnRH analogue. The mean final (n = 6) or latest (n = 4) height SDS was -1.36. The difference between final/latest height SDS and target height SDS was 0.93 +/- 1.13, i.e. less (p = 0.005) than the difference between height SDS and target height SDS at presentation, i.e. 1.72 +/- 1.26, indicating long-term catch-up growth.