Carl-Joachim Partsch

Consensus Statement on 21-Hydroxylase Deficiency from The European Society for Paediatric Endocrinology and The Lawson Wilkins Pediatric Endocrine Society

1Writing Committee: Peter E. Clayton, Royal Manchester Children’s Hospital, Manchester, UK; Walter L. Miller*,University of California, San Francisco, Calif., USA; Sharon E. Oberfield, Columbia University, New York, N.Y., USA;E. Martin Ritzen, Karolinska Institute, Stockholm, Sweden; Wolfgang G. Sippell*, University Children’s Hospital,Kiel, Germany; Phyllis W. Speiser, New York University, New York, N.Y. (*co-chairs)

Management and outcome of central precocious puberty

Precocious puberty is a condition which has both important and diverse consequences for affected children and their families. The impact of precocious pubertal development on the patients is both physical and psychological. Because of the potential for a rapid, dynamic course of the disease it is necessary to make a correct diagnosis without delay in order to allow a judgement about the prospective course of the disease in terms of rate of pubertal progression, statural growth, bone age progression, development of reproductive functions and psychosocial adjustment and well-being. It is not surprising that there has been a controversial discussion about the indications for treatment, as precocious puberty is characterized by a great diversity in clinical presentation, in underlying causes for precocious development and thus, also, in its long-term prognosis. In this paper, we review some of the salient clinical, laboratory, and radiological features of the possible causes of precocious puberty and discuss the current treatment options as well as the long-term outcome.

Statural growth in Williams-Beuren syndrome

The spontaneous growth of 165 patients (75 girls and 90 boys) with Williams-Beuren syndrome was analysed in a mixed longitudinal and cross-sectional manner. Mean (±1 SD) length at birth was 48.2±2.6 cm in girls (n=52) and 49.0±3.0 cm in boys (n=65). Intrauterine growth retardation (length below −2 SD of the normal population) was present in 35% of the girls and 22% of the boys. Poor growth was noted during the first 2 years of life. Until age 9 years in girls and 11 years in boys, mean growth followed the 3rd percentile. A pubertal growth spurt with normal growth rate was seen at age 10 years in girls and 13 years in boys, i.e. 1 to 2 years earlier than normal. Menarche also occurred earlier than normal at a mean age of 11.6±1.5 years (n=28). Mean adult height was 153.9±6.9 cm in girls (n=17) and 168.2±6.9 cm in boys (n=27), approximately corresponding to the 3rd percentile in both sexes and correlating with the genetic height potential (target height). The mean deficit of adult height compared to target height was 10.2 cm in girls and 9.1 cm in boys. Skeletal development progressed at an approximately normal rate in both sexes.

Longitudinal evaluation of growth, puberty, and bone maturation in children with Williams syndrome

OBJECTIVES To establish syndrome-specific growth curves and growth rate (GR) curves for Williams syndrome (WS) and define the pattern of bone maturation and pubertal development. METHODS In a prospective longitudinal study between 1990 and 1997, the growth data of 244 children with WS were collected: 295 values for GR were calculated for 74 girls and 331 values for 89 boys. RESULTS Mean GR of children with WS was below normal by 1 to 2 cm/y in the first few years of life. One group of girls (n = 20) experienced an early pubertal growth spurt at age 9 years (maximal GR, 7.8 +/- 2.1 cm/y; menarcheal age, 10.4 +/- 1.4 years). A second group (n = 5) showed the growth spurt at age 11 years (7.5 +/- 1.1 cm/y; menarcheal age, 12.6 +/- 1.3 years). In boys, peak height velocity (8.7 +/- 2.3 cm/y) occurred at age 11 to 12 years. Bone age was delayed in both sexes during childhood and accelerated markedly during puberty. Final height was 152.4 +/- 5.7 cm in girls (n = 38) and 165.2 +/- 10. 9 cm in boys (n = 43). CONCLUSIONS The syndrome-specific GR curves for WS showed a premature and abbreviated pubertal growth spurt in both sexes. This growth spurt was directly related to bone age acceleration during puberty. The data from this longitudinal study provide an overview of both the dynamics of growth and its course in children with WS.

Management of Congenital Adrenal Hyperplasia: Results of the ESPE Questionnaire

The management of children and adolescents with congenital adrenal hyperplasia (CAH) remains difficult. To assess the current European practice in diagnosis and management of CAH, an ESPE (European Society for Paediatric Endocrinology) survey was circulated in 2000/2001. The questionnaire was answered by 34% of ESPE members, representing 125 institutions which cared for 6,553 CAH patients. Paediatric endocrinologists, surgeons, gynaecologists, geneticists, and psychologists are involved in the immediate care of the CAH neonate and his family. 44% of centres take part in neonatal screening programmes. In families at risk, prenatal dexamethasone therapy is started at a median gestational age of 6 weeks in a median dose of 20 µg/kg/day. 53% reported maternal adverse events, 8% observed adverse fetal events. Regarding feminizing surgery, 33% reported simultaneous clitoric reduction and vaginoplasty during infancy. However, clitoridectomy is still reported by 13% of centres, and vaginal dilatations have been performed by 27%. Although 71% of female CAH patients with psychosexual problems, only 17% undertake routine psychodiagnostics and counselling. Hydrocortisone is the substance used for the treatment of CAH during growth in 84%; the median dose (mg/m²/day) is 17.5 in infants, 15 in children and adolescents, and 13.75 in adults. The glucocorticoid dose is increased two- to sixfold during intercurrent stress. Mineralocorticoid is administered in cases of clinically manifest salt wasting and of elevated plasma renin activity, to decrease high glucocorticoid doses, or according to genotype. All participating ESPE members feel the need for further improvement in prenatal diagnosis and treatment, compliance during puberty, screening programmes, psychological aspects, and corrective surgery.

Risk of sudden death in the Williams–Beuren syndrome

Williams–Beuren syndrome (WBS) is a genetic disorder characterized by a distinctive facial gestalt, mental retardation, mild growth deficiency, and cardiovascular disease. The occurrence of sudden death in the WBS is known from several case reports, but information about the risk of sudden death as derived from the data of a large cohort of patients is lacking. We analyzed the data of 293 WBS patients who had been treated for 43 years at the same two institutions. We thus collected 5,190 patient years without loss to follow‐up. During this period ten patients died. Five of them died from: reticulosarcoma (1), after accident (1), heart failure (1), following heart surgery (2). Of the remaining five patients, four died suddenly and one died of unknown cause suggestive of sudden cardiac death. Thus, the incidence of sudden death in our WBS cohort amounts to 1/1,000 patient years. This risk of sudden death is comparable to that following surgery for congenital heart disease, and is 25–100‐fold higher compared to the age‐matched normal population.

Anomalies of the abdominal aorta in Williams-Beuren syndrome – another cause of arterial hypertension

Abstract. Vascular disease in Williams-Beuren syndrome is based on an elastin arteriopathy which may cause stenoses in small and great vessels. This study presents the pattern of stenotic lesions of the abdominal aorta and the incidence of arterial hypertension. From 112 patients with Williams-Beuren syndrome followed since 1975, 25 patients were studied by aortography. The diameter of the thoracic aorta and the change in diameter to the iliac bifurcation were compared with normal data. Renal artery stenosis was suspected when the proximal vessel diameter was less than 50% of the distal diameter. Of the 25 patients, 20 had vascular stenosis of whom 19 patients were affected by segmental narrowing either of the thoracic aorta (n=9) or the abdominal aorta (n=7) or both (n=3). Hypoplasia of the abdominal aorta was characterised by the smallest diameters at the renal artery level and an increased diameter of the infrarenal abdominal aorta. A total of 11 patients had renal arterial stenosis, associated with narrowing of other aortic segments in 10 cases. Only one patient had a solitary stenosis of the renal artery. Arterial hypertension was diagnosed in 17 patients, 2 of them had no vascular lesions; in the remaining 15 patients stenosis was present in more than one segment (aorta 6, renal artery stenosis 1, both 8). Conclusion: narrowing of the abdominal aorta in patients with Williams-Beuren syndrome is a frequent morphological manifestation of the arteriopathy. Isolated renal arterial stenosis was rare, since it was more frequently combined with a narrowed aorta. Hypertension is a common symptom in the affected group and must be regarded as a manifestation of generalised arteriopathy rather than renal hypoperfusion.

Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function

Depot gonadotropin releasing hormone (GnRH) agonist (GnRHa) therapy is the treatment of choice for patients with central precocious puberty (CPP). It is still unclear whether long-term exposure to GnRHa is associated with impaired reproductive function in adulthood. The present study was performed on 46 women, former CPP patients, 12.5+/-3.7 years after the discontinuation of treatment with depot GnRHa. In a structured interview, we assessed general health status, clinical signs possibly associated with hyperandrogenism, menstrual cycle, gynaecological diseases and reproductive function. It appears that long-term treatment with depot GnRHa is safe and does not impair reproductive function. The risk of former CPP patients to develop hirsutism and/or polycystic ovary syndrome does not seem to be increased compared to the normal population but this issue needs to be addressed in further long-term follow-up studies.

Familial Williams-Beuren syndrome showing varying clinical expression.

Williams-Beuren syndrome (WBS) is a contiguous gene syndrome that occurs mainly sporadically, with an estimated frequency of 1:13,700 to 1:25,000 [Grimm and Wesselhoeft, 1980; Martin et al., 1984; Udwin, 1990]. The cases of monozygotic twins concordant for WBS and dizygotic twins discordant for the syndrome have been reported. In addition, a few familial cases have been described since 1993. The clinical diagnosis has been supported by molecular genetic findings in only two patients, however. We herein report on two families in which the WBS was inherited in girls from their mothers. All four patients showed the typical hemizygous deletion at 7q11.23 [46,XX, ish,del(7)(q11.23q11.23) (ELN/LIMK1/D7S-613x1, D7S486/D7S522x2)], but the clinical picture was strikingly variable within and between families.

Gonadotropin-Releasing Hormone Analogue Treatment for Precocious Puberty

Central precocious puberty (CPP) is the premature onset of puberty due to a precocious activation of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. This condition results in acce