Search

Investigations were carried out in 2 women of 17 and 18 years with primary amenorrhea, normal external female genitalia and delayed secondary sexual characteristics, for the reasons for delayed puberty. The 17-year-old patient had reduced values of FSH, LH and oestradiol. This disturbance in the hypothalamo-hypophysary axis was caused by hydrocephalus. Menarche occurred following drainage of the fluid. The 18-year-old patient had raised values ofFSH and LH and a lowered oestradiol value. There was therefore a disfunction existing at ovarian level, which appeared to be caused by an XX-gonadal dysgenesis. The patient was treated with hormones which led to breast development and menarche taking place. The cause ofprimary amenorrhea can mainly be divided into three categories: constitutional delayed puberty, delayed puberty due to hypogonadotropic hypogonadism, or delayed puberty due to hypergonadotropic hypogonadism. A carefully taken medical history, together with determination of the serum levels of FSH and LH, is helpful in differentiating between these categories. Subsequently, structured clinical management must be performed in order to approach the differential diagnosis of each of these categories, which will then be followed by the final diagnosis.

Androgen insensitivity is an X-linked disorder of male sexual differentiation resulting from a defective androgen receptor. Spinal and bulbar muscular atrophy (Kennedy's disease) is an X-linked disease, resulting from expansion of the polyglutamine stretch in the N-terminal part of the androgen receptor. Mutation analysis confirms the clinical diagnosis of androgen insensitivity and enables carrier detection and prenatal diagnosis. Kennedy's disease, with its diagnostic problem of clinical variability, is diagnosed or excluded when an expanded CAG-repeat is present or absent in exon 1 of the androgen receptor. Molecular testing can be used for carrier detection and genetic counselling.

The importance of the secretion and action of androgens during the critical period of male sexual development is exemplified in patients with androgen insensitivity syndrome. Their karyotype is always 46XY. In 2 sisters, aged 11 and 13 years, the androgen insensitivity syndrome was diagnosed based on an androgen receptor gene mutation. Ambiguous genital development of a new-born was shown to be due to a lack of testosterone production, based on a luteinizing hormone receptor gene mutation. Finally, in a phenotypically female new-born a gene mutation of 17-beta hydroxysteroid dehydrogenase type 3 was found to be responsible for insufficient testosterone synthesis during embryonic development. The presentation of a patient, and specifically a neonate, with abnormal genital development represents a difficult diagnostic and therapeutic challenge. Referral to a centre with experience in the diagnosis and management of disorders of sexual development is advised where the emphasis should be on psychological and genetic counselling.

Léri-Weill dyschondrosteosis is a pseudodominant hereditary skeletal dysplasia associated with haploinsufficiency of the SHOX gene. The SHOX gene is located on the pseudoautosomal region of both the X-chromosome and the Y-chromosome, and belongs to the homeobox genes, which code for transcription factors involved in early foetal development. Mutations in the SHOX gene, especially deletions, are detected in approximately 60% of patients with Léri-Weill dyschondrosteosis. The SHOX gene is also involved in skeletal abnormalities in Turner syndrome and possibly plays a role in idiopathic short stature.

Children of constitutionally tall stature may experience serious problems related to their height. Treatment with high dose sex steroids may be considered in order to limit final adult height. Prediction of adult height plays a central part in the management of children of tall stature. Various aspects of height prediction in children of tall stature are discussed. The height reducing effect varies between studies from 2 to 10 cm. Recently, in a large Dutch study the mean effects of therapy were 0.7 and 2.4 cm for boys and girls respectively. The effect depended on the bone age at start of treatment. Beyond a critical bone age of about 14 years treatment had no effect. Minimal age for intervention is 9.5-10 year for boys and 9.0-9.5 year for girls. Recommended treatment for boys is 250 mg testosterone esters i.m. per week and for girls ethinyloestradiol orally 200 micrograms per day in combination with medroxyprogesterone or dydrogesterone (both 5-10 mg per day) during the first 12-14 days of the cycle. Treatment has to be continued until complete closure of the epiphyses. While side effects during hormonal therapy are frequent, they are mostly temporary and mild and seldom lead to cessation of therapy. So far there have been no indications of adverse effects on, for instance, gonadal function.

Persistent Müllerian duct syndrome (also known as uterine inguinal hernia) is described and two cases are reported. In this rare type of male pseudohermaphroditism there is no disturbance of either primary or secondary external masculinization. Consequently, this anomaly is always diagnosed incidentally, generally at operation for cryptorchidism or inguinal hernia. In addition to bilateral normal testes, these patients possess a uterus with two uterine tubes. The persistence of the internal female genitalia is caused by the insufficiency of the MIF hormone (Müllerian Inhibiting Factor). Early orchiopexy is recommended. Removal of the female internal genitalia is seldom required.

We describe three patients in whom at the age of 4-7 yrs the diagnosis adrenogenital syndrome (21-hydroxylase deficiency) was made. There was no salt-loss. Two boys presented with precocious pubic hair development and increased growth velocity and bone maturation. The third patient was a severely virilized girl raised as a boy until she was 4 yrs old. Following an extensive psychiatric evaluation, it was decided to raise her as a girl and feminoplasty was performed. Clinical and biochemical evidence of central precocious puberty was present in one boy at the time of diagnosis at age 7 and developed under hydrocortisone substitution therapy in the two other patients. The precocious puberty was treated in two patients with the anti-androgen cyproterone acetate. In one boy suppression of pituitary gonadotropin secretion was obtained by LH-RH analogue (Buserelin) treatment.

The diagnostic work-up of a patient with (familial) hypocalciuric hypercalcemia (FHH) is discussed. The patient showed no clinical signs of hypercalcemia. There were no indications of vitamin D intoxication. In the first degree family members no hypercalcemia was found. Physical examination was normal. In contrast to hyperparathyroidism, FHH is usually symptomless. Furthermore, FHH is characterized by a normal chloride/phosphate ratio, a normal, but relatively high, serum parathyroid hormone level, a relatively low urinary calcium excretion, a calcium-creatinine clearance ratio less than 0.01 and a normal cyclic AMP excretion.

Precocious puberty is a stressful event for patient and environment. The diagnostic evaluation will be discussed. LHRH analogs will give a new approach in the treatment of central precocious puberty.