Inge François

Adrenarche and Fetal Growth

Dehydroepiandrosterone sulfate (DHEAS) is prenatally secreted by the fetal adrenal, is an indicator of adrenarche from late childhood onward and is a marker of the individual hormonal milieu in the adult. The regulation of DHEAS secretion is still poorly understood. We postulated that serum DHEAS concentrations in children may be related to fetal growth. To test this hypothesis, serum DHEAS was measured at a median age of 8.2 y (range 5.8-16.0 y) in 13 pairs of discordant siblings after twin (n = 8), triplet(n = 4), or quadruplet (n = 1) pregnancy. At birth, one of each pair was small for gestational age (SGA) and the other had an appropriate weight (AGA); weight of the smallest infant was a median 67% (range 33-80%) of that of the largest sibling. In all 10 pairs with similar weight (≤ 1 SD difference) at the time of sampling, serum DHEAS concentration in the SGA child was higher (median 2-fold increase; range 1.1-7; p = 0.002) than in the AGA sibling. Conversely, in the 3 pairs with still discordant weight (>2 SD difference), serum DHEAS levels in SGA children were lower than in AGA children. In conclusion, the presented findings, which account for both prenatal and postnatal weight gain, unmask a link between adrenarche and fetal growth. This relationship further supports the concept of early endocrine “programming” and extends this principle to adrenarche.

Low Birth Weight and Subsequent Male Subfertility

Male subfertility often remains unexplained. Severe intrauterine growth retardation has previously been linked to hypergonadotropic hypogonadism. We examined whether reduced fetal growth, as judged by low birth weight, is associated with unexplained male subfertility later in life. Birth weight and gestational age were obtained by questionnaire from male partners of couples consulting for subfertility, and were transformed into birth weight SD scores. Men with normal semen analysis (n = 128) had a median birth weight SD score of 0.0 (P25-P75 range: -0.7 to 1.0), comparable to that of men with explained subfertility (n = 28), and higher (p= 0.012) than that of men with unexplained subfertility (n = 32; median -0.5 SD score; P25-P75 range: -0.9 to -0.1). These results extend the link between reduced fetal growth and male subfertility to a range of birth weight that is well within normality. The pathophysiologic mechanism governing this association now remains to be unraveled.

Androgens and fetal growth

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.

Male Pseudohermaphroditism Related to Complications at Conception, in Early Pregnancy or in Prenatal Growth

We examined whether male pseudohermaphroditism, when unexplained, is associated with reduced prenatal growth. Birth weight SD scores of 29 children with male pseudohermaphroditism were compared. The scores of children with an unexplained condition (median –2.1 SD) were found to be lower (p = 0.0001) than those of children with an explained condition (median –0.4 SD). In the majority of cases of unexplained male pseudohermaphroditism, there was a complicated history before conception or in early pregnancy. In conclusion, hitherto unexplained male pseudohermaphroditism was found to be associated with reduced prenatal growth and complications at conception or in early pregnancy.

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.

Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations

Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11‐ and KRAS‐negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1‐positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.

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 treatment of short children born small for gestational age

Short children born small-for-gestational-age (SGA) appear to be at an increased risk of having a poly-endocrinopathy, including a degree of growth hormone (GH) deficiency and/or insulin-like growth factor 1 (IGF-1) resistance. Among GH-deficient children, those born SGA present a lower growth response to GH therapy than those not born SGA. The growth response of short SGA children to GH treatment does not appear to depend significantly on the secretory status of GH (as judged by provocative testing), indicating that the SGA condition (IGF-1 resistance) predominates over the availability of endogenous GH in determining the short stature of the majority of these children. When a higher than replacement dose of GH is administered, the growth response of short SGA children matches that of GH-deficient non-SGA children, indicating that the IGF-1 resistance towards growth can be overcome, and that a normal stature can be obtained, at least throughout childhood. It is anticipated that, increasingly, the indications and the doses for GH therapy in children will become interlinked with the emerging principles of endocrine programming in early life.

Global distribution of the most prevalent deletions causing hypotonia-cystinuria syndrome

Hypotonia–cystinuria syndrome (HCS) is a recessive disorder caused by microdeletions of SLC3A1 and PREPL on chromosome 2p21. Patients present with generalized hypotonia at birth, failure to thrive, growth retardation and cystinuria type I. While the initially described HCS families live in small regions in Belgium and France, we have now identified HCS alleles in patients and carriers from the Netherlands, Italy, Canada and United States of America. Surprisingly, among the nine deletions detected in those patients, only one novel deletion was found. Furthermore, one previously described deletion was found six times, another twice. Finally, we have investigated the frequency of both deletions using a random Belgian cohort. Given the global occurrence, HCS should be considered in the differential diagnosis of neonatal hypotonia.

Association of hyperprolinaemia type I and heparin cofactor II deficiency with CATCH 22 syndrome: evidence for a contiguous gene syndrome locating the proline oxidase gene

SummaryIncreased proline levels were found in plasma of a girl with slight psychomotor retardation, epilepsy, obesity, scoliosis, hypocalcaemia, variable lymphocytopenia and facial dysmorphy suggestive of CATCH 22 syndrome. Fluorescencein situ hybridization indicated the presence of a submicroscopic 22q11 deletion, confirming this diagnosis. Further investigation showed evidence that the patient was heterozygous for heparin cofactor II deficiency and for hyperprolinaemia type I, a proline catabolic disorder due to proline oxidase deficiency. This association extends the CATCH 22 syndrome and suggests that expression of the proline oxidase gene depends on the chromosome 22q11 region.