M. Craen

Psychosocial Functioning, Self-Perception and Body Image and Their Auxologic Correlates in Growth Hormone and Oestrogen-Treated Young Adult Women with Turner Syndrome

Background: Few data are available on the psychosocial status of growth hormone (GH) and oestrogen treated women with Turner syndrome (TS). In this study, we evaluated psychosocial functioning, self-concept and body image in GH and oestrogen treated young adult women with TS and we studied the relationship with auxological parameters. Patients and Methods: Thirty women with TS (mean ± SD age: 22.1 ± 2.4 years), all treated with GH and oestrogens if indicated, and an age-matched reference group of 44 non-Turner female students (age: 20.5 ± 2.1 years) completed 3 questionnaires evaluating, respectively, behavioural and emotional problems (Young Adult Self Report), self-concept (Self Perception Profile for College Students) and body-image (Body Attitude Scale). Results: TS patients did not report more behavioural and emotional problems compared to the non-TS females except for attention problems; they even reported fewer problems on some subscales (somatic complaints, thought problems, delinquent behaviour). TS patients did not differ from the non-TS female group in their bodily satisfaction. TS patients, particularly patients with a 45,X karyotype, perceived themselves as less socially competent. BMI was significantly related to the appraisal score of the Body Attitude Scale, whereas height was not related to any of the evaluated psychosocial parameters. Conclusion: The psychosocial adaptation of young adult women with TS, diagnosed at an early age and treated during childhood with GH and oestrogens if indicated, appears to be quite satisfactory. Follow-up of adult TS patients should not neglect the problem of overweight and associated psychosocial consequences.

GROWTH HORMONE DEFICIENCY AND PREMATURE THELARCHE IN A FEMALE INFANT WITH KABUKI MAKEUP SYNDROME

We report on a girl with the kabuki makeup syndrome, including short stature, premature thelarche and partial growth hormone deficiency of hypothalamic origin, without stalk interruption. Treatment with recombinant human growth hormone resulted in an increase of annualized growth velocity from 3.6 to 11.2 cm. The kabuki makeup syndrome may be associated with hypothalamopituitary dysfunction.

Growth hormone therapy in pre-pubertal children with Noonan syndrome : first year growth response and comparison with Turner syndrome

We studied the growth‐promoting effect of treatment with recombinant human growth hormone in 23 prepubertal children with Noonan syndrome, aged between 5. 4 and 14. 3 y, and all with a height < 1. 4 SD for Tanner standards. The growth response and skeletal maturation after 1 y of recombinant human growth hormone treatment (0. 15 U/kg/day given by daily injection) in the Noonan syndrome patients was compared with the auxological changes observed in a group of 17 girls with Turner syndrome with a comparable age and height deficit who were treated with recombinant human growth hormone in a similar way. During 1 y of treatment, the mean ± SD height velocity increased by 4. 0 ± 1. 6 cm/y in the Noonan syndrome group and by 3. 6 ± 1. 3 cm/y in the Turner syndrome group. Height SDS for chronological age in the Noonan syndrome group increased by 0. 53 ± 0. 46 (p < 0. 001). In the Noonan syndrome patients the changes in height velocity were positively related to birthweight (r= 0. 48, p < 0. 05). The changes in height velocity or height SDS were not related to the age, height deficit or a delay in bone age maturation at start of treatment. In neither the patients with Noonan syndrome nor Turner syndrome was an acceleration of bone maturation found. We conclude that treatment with recombinant human growth hormone in pre‐pubertal NS patients induces an increase in height velocity and height SDS comparable to that observed in Turner syndrome girls.

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.

GROWTH PROMOTING EFFECT OF GROWTH HORMONE AND LOW DOSE ETHINYL ESTRADIOL IN GIRLS WITH TURNER SYNDROME: FINAL HEIGHT RESULTS

In 1987 a multicenter trial was started to evaluate the effect of daily s.c. rhGH treatment (0.15 IU/kg/day Genotonorm, Kabi Pharmacia, Sweden) in 40 girls with Turner syndrome (TS) (mean±SD age: 11.3±2.6 yrs). Twenty randomly selected girls received in addition 25 ng/kg/day ethinylestradiol (EE2) orally. From the 3rd year of treatment puberty was induced with 100 ng/kg/day EE2 in the girls with a bone age older than 11 years. Thirty-six patients have been followed for 5 years. Except early breast budding in 9 out of 20 girls treated with rhGH and 25 ng/kg/day EE2, no differences were found between the patients treated with rhGH alone and those also treated with low dose EE2. In 28 patients with a bone age above 13 yrs, height attained 5 years after the start of rhGH treatment is 150.5±4.4 cm. This is higher (P<0.001) than the adult height of 144.8±5.8 cm of 43 untreated TS girls. In these 28 girls, the difference in height attained after 5 years of treatment and corrected mid parental height is 10.8±4.8 cm, which is less (P<0.001) than in untreated adult TS patients (16.2±4.8 cm). These results provide further evidence that treatment with rhGH increases final height in TS girls.

Assessment of Gonadotropin-deficiency in Pituitary Dwarfism

Fifty three patients with idiopathic (45) and organic (8) hypopituitarism, 43 boys and 10 girls, were studied during treatment with hGH. The gonadotrophin responses to GnRH (25 μg/m2) and serum levels of DHEA-s were measured yearly ; 15 patients remained prepubertal whereas 38 patients were studied before and during puberty occuring either spontaneously (11) or induced (27) by testosterone propionate (100 mg/mth) or ethinyloestradiol (10 μg/day)Gonadarche and adrenarche were dissociated in some patients : among the 11 patients with spontaneous gonadarche, 2 had no previous biological adrenarche ; among the 27 gonadotrophin deficient (G.D.) patients, 9 had spontaneous adrenarche.In prepubertal patients who were subsequently confirmed to be G.D., 27 GnRH tests were performed ; 23/27 integrated responses (I.R.) of FSH were found to be markedly lower than those observed in prepubertal controls of both sexes. In 9/27, I.R. of LH were below the control range. However, when in boys, I.R. of LH were analyzed according to bone age, 17/19 were below the lower limit of the control range.These data might stress the importance of calculating I.R. of FSH to GnRH in hypopituitary patients in order to predict gonadotrophin deficiency.