Jp Bourguignon

Longitudinal study of behavioral and affective patterns in girls with central precocious puberty during long-acting triptorelin therapy

Abstract The aim of the present study was to evaluate the behavioral and affective characteristics and the changes in psychosocial functioning resulting from precocious puberty in 15 girls with central precocious puberty treated for 2 y using the GnRH agonist long‐acting triptorelin, and in 5 untreated girls. After diagnosis of precocious puberty at 6.6–10.4 y of age, height, weight and pubertal development were evaluated at 3‐month intervals over 2 y. Semi‐structured interviews were carried out with the patient, the parents and the pediatric endocrinologists at 1, 8, 16 and 24 months after diagnosis. Standardized questionnaires (Child Behavior Checklist, Self‐esteem Inventory) were administered at 1 and 24 months or 16 and 24 months, respectively. There was a mean 1.5‐y delay between the observation of signs of puberty as reported by the parents and the diagnosis of precocious puberty at the first consultation of a pediatric endocrinologist. Before follow‐up, all 20 girls were very concerned about physical differences from peers, particularly breast development. During therapy, breast regression to minimal or absent development occurred in 5/15 treated patients, who then no longer felt embarrassed about pubertal development in contrast to the other patients. Fear of sexuality remained obvious throughout the study in most patients. Feelings of loneliness and exemplary behavior were observed and tended to decrease in the treated patients and to increase in the untreated patients. Elevated scores of withdrawal, anxiety/depression and somatic complaints at Child Behavior Checklist were still observed after 2 y. These changes in behavioral and affective characteristics appeared to be related neither to height and weight, nor to development of pubic hair, which progressed in most patients. After 2 y, the physical differences remained a concern for 13 girls and the risk of short adult stature for 6. In summary, some behavioral and affective characteristics and particularities in psychosocial functioning are observed in girls with precocious puberty. During treatment with long acting triptorelin, problematic behavior and functioning decrease slightly, particularly in the few girls showing breast regression to minimal or absent development.

Health and Psychosocial Status of Patients with Turner Syndrome after Transition to Adulthood: The Belgian Experience

Background: Most girls with Turner syndrome (TS) are intensively followed by paediatricians, but are lost to follow-up when they reach adulthood. To gain insight into the adult medical and psychosocial situation, we performed a survey in young adult TS patients. Patients and Methods: A questionnaire concerning current health status, education, occupation and living situation was sent to 160 young adult TS women, all treated during childhood with GH and oestrogen if needed. Results: We received 102 completed questionnaires. Mean ± SD age at reception of the questionnaire was 23.4 ± 3.3 years, height 153.3 ± 5.2 cm, body mass index 23.7 ± 4.9 kg/m². Age and auxological parameters were comparable between responders and non-responders. Thirteen (12.7%) responders were not under regular medical care; 15 (14.7%) were seen by a general practitioner, while 28 (27.4%) needed several specialists. Forty-one (40.2%) patients reported health problems. The most frequently reported problem was hypertension (10.7%), followed by hypothyroidism (5.8%) and back problems (4.9%). Twenty-four (23.5%) of the 41 patients were taking medication for the indicated health problems. Twenty-six (25.5%) women had undergone spontaneous puberty; 16 of them reported spontaneous menstruations while 10 received oestrogen replacement therapy. Of the 76 women with induced puberty, 11 (14.5%) were not taking any oestrogen anymore. Compared with the general population, more TS women attended university and more obtained higher education. Forty-six women (45.1%) were working full-time, 7 (6.9%) were unemployed, and 4 (3.9%) received an allocation. Seventy (68.6%) patients were still living with their parents, while 18 (17.6%) were living together or married, and 14 (13.7%) were living alone. Conclusions: The transition of adolescents with TS to adult medical care is not optimal in Belgium. Although 40.2% of these young women reported health problems, 12.7% did not consult any physician. Many TS women did not take oestrogen replacement therapy. A specialized multidisciplinary approach for adults with TS is needed in order to optimize health and psychosocial status in these women.

Final Height in Children with Idiopathic Growth Hormone Deficiency Treated with Recombinant Human Growth Hormone: The Belgian Experience

Background: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied. Patients/Methods: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5–0.7 IU/kg/week (0.17–0.23 mg/kg/week) from the mean ± SD age of 11.9 ± 3.1 years during 5.1 ± 2.1 years. Results: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was –0.7 ± 1.1 SDS, being 170.4 ± 7.2 cm in boys and 158.0 ± 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 ± 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 ± 7.0 cm vs. 27.5 ± 6.6 cm (p < 0.005); girls: 9.6 ± 7.4 cm vs. 22.2 ± 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty. Conclusions: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5–0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty.

Factors Contributing to the Impairment of Growth in Children with Acute Lymphoblastic Leukemia

Growth was studied in 88 long-term survivors of acute lymphoblastic leukemia who had been treated with three different regimens of therapy. The following time periods were evaluated: (1) during therapy; (2) between the end of therapy and the onset of puberty, and (3) between the onset of puberty and the most recent observation. We found: (1) a reduction of height SDS during therapy, related to the irradiation dose used; no significant effect of the duration of the therapy could be established; (2) a normal growth rate during the second time period studied for the total group, but a further decrease in height SDS for those found to be growth hormone deficient after therapy (47%), and (3) a further decrease in height SDS during puberty. The timing of puberty in the female patients was normal. We conclude that in patients treated for acute lymphoblastic leukemia, growth impairment has several components, different in timing and mechanism.

Variations in pituitary-gonadal suppression during intranasal buserelin and intramuscular depot-triptorelin therapy for central precocious puberty

Heinrichs C, Craen M, Vanderschueren‐Lodeweyckx M, Malvaux P, Fawe L, Bourguignon JP. Variations in pituitary‐gonadal suppression during intranasal buserelin and intramuscular depot‐triptorelin therapy for central precocious puberty. Acta Pædiatr 1994;83:627–33. Stockholm. ISSN 0803–5253

Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients

To the Editor: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus accounting for approximately 1–2% of noninsulin dependent diabetes. It is characterized by early-onset pancreatic b-cell dysfunction and autosomal dominant inheritance. MODY is a genetic heterogeneous condition for which today seven causal genes have been identified; the hepatocyte nuclear factor 4a (HNF-4a) causing MODY1 (1), the glucokinase enzyme (GCK) responsible for MODY2 (2), the hepatocyte nuclear factor 1a (HNF-1a or TCF1) causing MODY3 (3), insulin promotor factor-1 (IPF1; MODY4) (4), transcription factor HNF1b (TCF2; MODY5) (5), Neuro1D (MODY6) (6) and the carboxyl ester lipase (CEL) gene (7). In Europe, GCK-MODY and HNF-1a-MODY are the most prevalent forms (8–11), with their prevalence mainly depending on the way of recruitment. We have performed molecular screening of the GCK gene in 161 patients belonging to 124 families, referred to our centre between 2002 and 2005 from hospitals in Belgium and Luxembourg. All probands fulfilled at least two of the following criteria: early-onset hyperglycaemia (age of onset ,40 years), the absence of beta cell autoantibodies and a positive familial history for diabetes, with at least two successive generations affected. Polymerase chain reaction amplification (primers and conditions available upon request) and sequence analysis of exon 1a and exons 2 to 10 of the GCK gene (Genbank XM_041001) resulted in the detection of a mutation in 33 of the 124 probands. Additional mutation analysis performed in available family members of the probands showed cosegregation of the GCK mutations, with the MODY phenotype examined in all the families. 19 different mutations were identified (Table 1), including eight previously described missense mutations: p.Arg36Trp (12), p.Cys129Tyr (9), p.Arg191Trp (13), p.Gly223Ser (9), p.Val226Met (14), p.Ala378Thr (15), p.Ser441Trp (9) and p.Arg447Gln (15). Three of the 11 new GCK mutations identified during this study are clearly inactivating, as they result in pre-mature termination of translation: c.171delG, c.663673dupGGTCGGCATGA and c.1261delG cause pre-mature termination codons after respectively 85, 227 and 429 amino acids. Two splice site mutations (680-1 G.A and 680-6 C.A) may also result in aberrant nonfunctional GCK transcripts as theoretical splice site prediction (16) shows decrease in splice acceptor consensus value for both 680-1 C.A (from 0.869 to 0.662) and 680-6 C.A (from 0.869 to 0.801) mutations. Unfortunately, no RNA was available to confirm this. Six new missense mutations (p.Phe152Leu, p.Ala188Val, p.Met202Arg, p.Asn231His, p.Leu315Phe and p.Cys434Phe) were detected in diabetic probands and were found to be absent in our control population (100 chromosomes, Belgian origin). All six missense mutations were predicted pathogenic by the theoretical prediction programme SIFT (17), while the Polyphen theoretical prediction programme (18) predicts a damaging effect for four of them, but not for p.Ala188Val and p.Leu315Phe. However, these two mutations segregate with diabetes in the families tested and are highly conserved in the glucokinases or hexokinases of all the mammalians. Moreover, mutations affecting the alanine188 residue have been reported in diabetic patients before (19, 20). The same is true for the cysteine residue at position 434 (10, 20). The p.Phe152Leu and p.Asn231His missense mutations contribute to the glucose binding site and are believed to disrupt glucose binding.