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NORMAL PUBERTAL DEVELOPMENT:
1. Appearance of secondary sexual characteristics
1a. Thelarche (breast development at age 10.5-10.9 years) Initial event.
1b. Pubarche ( pubic and axillary hair at age 11.2 years) Sometimes initial.
1c. Menarche (13.0-14.5 years)
2. Linear growth (rapid)
3. Fertility.
Stages of Development of Secondary Sexual Characteristics
Breast development :
Stage 1. Prepubertal: papilla. elevation.
Stage 2. Budding , enlargement of areola diameter
Stage 3. Further enlargement and elevation of breast and areola.
Stage 4. Projection of areola and papilla.( Secondary mund of areola an
papilla)
Stage 5. Mature stage: projection of papilla.
Pubic hair development:
Stage 1. Prepubertal: vellus over pubis.
Stage 2. Sparse growth of long, slightly pigmented, downy hair
Stage 3. Considerably darker, coarser. Hair spreads over junction of pubis
Stage 4. Hair adult in type. No spread to medial surface of thighs
Stage 5. Adult (quantity and type). Distribution of feminine pattern.
PRECOCIOUS PUBERTY
Development of secondary sexual characteristics before the age of 8 years (in girls). Rapid linear growth and premature
skeletal maturation, usually resulting in short adult stature.
CLASSIFICATION OF PRECOCIOUS PUBERTY (PP)
A. According to gender:
A1. Isosexual PP (consistent with the sex of the patient)
A2. Heterosexual (due to androgen excess. eg. Adrenogenital syndrome)
B. According to clinical features:
B1. Total or complete PP (telarche, pubarche and menarche)
B2. Partial or incomplete ( isolated telarche, pubarche or menarche)
C. According to gonadotropin dependence:
C1.Central or gonadotropin dependent. activation of hypothalamic pituitary axis)
-CNS tumors, irradiation, trauma.
-Idiopathic ( MOST COMMON form . 80% of CPP are idiopathic)
C2. Peripheral or gonadotropin independent. (lack of activation of hypothalamic pituitary axis)
-Ovarian cysts, tumors (granulosa), luteoma
-Iatrogenic (accidental ingestion of hormones on a continued basis)
-McCune Albright syndrome
-Adrenal (heterosexual PP)
EVALUATION OF THE PATIENT WITH PRECOCIOUS PUBERTY:
1. History. Physical examination, neurologic examination, pattern of height and weight, queries about prior CNS
trauma, radiation exposure, seizures; exposure to exogenous sex steroids and family history.
2. Laboratory studies ( FSH, LH, DHE, DHES, TSH, T4, hCG)
3. Thyroid function tests
4. GnRH testing
5. Bone Age ( x-ray to assess bone age)
6. Images ( Ultrasonography, CT or MRI)
7. Others
THERAPEUTIC AGENTS TO REVERSE SEXUAL PRECOCITY:
1. Inhibitors of LH/ FSH production ( GnRH agonists, Medroxiprogesterone Acetate, Cyproterone Acetate)
2. Inhibitors of andreogen estrogen production( Ketoconazole, Medroxiprogestrone Acetate, Spironolactone, Testo
lactone)
3. Inhibitors of estrogen androgen action ( Cyproterone Acetate, Tamoxifen, Flutamide, Spironolactone).
Eur J Pediatr 1999 May;158(5):367-70
Cirrhosis in a child with hypothalamic syndrome and central precocious puberty treated with cyproterone acetate.
Garty BZ, Dinari G, Gellvan A, Kauli R
Department of Paediatrics B, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv
University, Petah Tiqva, Israel.
[Medline record in process]
Before the advent of gonadotropin-releasing-hormone analogues, cyproterone acetate (CPA) had been widely prescribed
for the treatment of precocious puberty. Although it is usually well tolerated, liver toxicity has been recognized
as a complication of its long-term use. We report the occurrence of cirrhosis in a 10-year-old boy with hypothalamic
syndrome and precocious puberty who was treated with CPA for over 50 months. Despite discontinuation of the medication,
the liver disease progressed. The patient died of sepsis and multiorgan failure at the age of 14 years. This is
the first paediatric report of substantial liver damage and liver toxicity progressing to cirrhosis associated
with CPA treatment. CONCLUSION: Prolonged cyproterone acetate treatment may induce cirrhosis. Monitoring
of liver function both during treatment and for several months after discontinuation of therapy is recommended
Arch Dis Child 1999 Mar;80(3):231-4
Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing
hormone agonist depot.
de Brito VN, Latronico AC, Arnhold IJ, Lo LS, Domenice S, Albano MC, Fragoso MC, Mendonca BB
Developmental Endocrinology Unit, Sao Paulo University Medical School, Brazil.
The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting
of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum
or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty
(GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical
signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the
mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age
was -0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged
from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were
treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven
of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs.Mol Genet
Metab 1999 Feb;66(2):137-41
Glucocorticoid resistance in premature pubarche and adolescent hyperandrogenism.
Witchel SF, Smith RR
Children's Hospital of Pittsburgh, University of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania, 15213,
USA.
To determine whether glucocorticoid resistance due to mutations in the glucocorticoid receptor (GRL) gene is associated
with premature pubarche, hirsutism, or oligo/amenorrhea, we performed single-strand conformational polymorphism
analysis of genomic DNA obtained from 25 children and 16 adolescent girls referred for the evaluation of premature
pubarche, hirsutism, or oligo/amenorrhea. A missense mutation, N363S, and a presumed polymorphism in the 3'-UTR
of exon 9alpha were identified. We conclude that glucocorticoid resistance due to GRL mutations is an infrequent
cause of mild hyperandrogenism. Copyright 1999 Academic Press.
suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had
a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems
that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP
due to HH.
Eur J Pediatr 1999 Feb;158(2):123-6
Imaging of McCune-Albright syndrome using bone single photon emission computed tomography.
Kairemo KJ, Verho S, Dunkel L
Department of Clinical Chemistry, University Central Hospital, Helsinki, Finland.
McCune-Albright syndrome is a rare disorder caused by a somatic, constitutively activating mutation in the gene
(GNAS1) encoding the subunit of the signal transducing guanine nucleotide binding protein (G protein). The condition
is characterized by polyostotic fibrous dysplasia, cafe-au-lait pigmentation and multiple endocrine hyperfunction,
most commonly gonadotropin-independent precocious puberty in girls. Our patient, a 16-year-old male, with radiologically
confirmed polyostotic fibrous dysplasia in cranium, thoracic and pelvic girdles, spine and extremities was studied
using planar 99mTc-hydroxymethyldiphosphonate bone scintigraphy and single photon emission computed tomography.
Using bone scintigraphy, an unusually extensive and asymmetric fibrous dysplasia was observed in the cranium, face,
ribs, femur, humerus, ulna, tibia and the vertebral column, all on the left side. The whole body scan revealed
only a few foci on the right side. Single photon emission computed tomography demonstrated extensive unilateral
involvement in the base of the skull, facial bones, maxilla and mandible. All the lesions reached only the midline.
These findings formed the basis of further treatment, eg. reconstructive surgery of facial asymmetry. CONCLUSION:
McCune-Albright syndrome should be considered in the differential diagnosis when interpreting extensive unilateral
predominance in paediatric bone scans.J Clin Endocrinol Metab 1999 Feb;84(2):449-52
Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues
and growth hormone.
Pasquino AM, Pucarelli I, Segni M, Matrunola M, Cerrone F
Pediatric Department, University La Sapienza, Rome, Italy.
GnRH analogues (GnRHa) represent the treatment of choice in central precocious puberty (CPP), because arresting
pubertal development and reducing either growth velocity (GV) or bone maturation (BA) should improve adult height.
However, in some patients, GV decrease is so remarkable that it impairs predicted adult height (PAH); and therefore,
the addition of GH is suggested. Out of twenty subjects with idiopathic CPP (treated with GnRHa depot-triptorelin,
at a dose of 100 microg/kg im every 21 days, for at least 2-3 yr), whose GV fall below the 25th percentile for
chronological age, 10 received, in addition to GnRHa, GH at a dose of 0.3 mg/kg x week s.c., 6 days weekly, for
2-4 yr; and 10 matched for BA, chronological age, and duration of GnRHa treatment, who showed the same growth pattern
but refused GH treatment, served to evaluate the efficacy of GH addition. No patient showed classical GH deficiency.
Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 in GnRHa plus GH vs. 13.0 +/-
0.1 yr in the control group. At the conclusion of the study, all the patients had achieved adult height. Adult
height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of
over 15 yr. Patients of the group treated with GH plus GnRHa showed an adult height significantly higher (P <
0.001) than pretreatment PAH (160.6 +/- 1.3 vs. 152.7 +/- 1.7 cm). Target height (TH) was significantly exceeded.
The group treated with GnRH alone reached an adult height not significantly higher than pretreatment PAH (157.1
+/- 2.5 vs. 155.5 +/- 1.9 cm). TH was just reached but not significantly exceeded. The gain in centimeters obtained,
calculated between pretreatment PAH and final height, was 7.9 +/- 1.1 cm in patients treated with GH combined with
GnRHa; whereas in patients treated with GnRHa alone, the gain was just 1.6 +/- 1.2 cm (P = 0.001). Furthermore,
no side effects have been observed either on bone age progression or ovarian cyst appearance and the gynecological
follow-up in the GH-treated patients (in comparison with those treated with GnRHa alone). In conclusion, a gain
of 7.9 cm in adult height represents a significant improvement, which justifies the addition of GH for 2-3 yr during
the conventional treatment with GnRHa, especially in patients with CPP, and a decrease in GV so marked as to impair
PAH, not allowing it to reach even the third centile.
J Clin Endocrinol Metab 1999 Feb;84(2):415-23
Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20
untreated patients.
Palmert MR, Malin HV, Boepple PA
Department of Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
A small number of young girls with unsustained or slowly progressive puberty have been described, but few data
regarding their final heights and adult reproductive function have been reported. We have conducted a study that
delineates the initial presentation and 12-yr follow-up of 20 patients who initially presented with unsustained
or slowly progressive puberty as young girls. The patients were first seen between 1984-1987. They all underwent
extensive clinical and hormonal studies, including frequent blood sampling and pelvic ultrasound to characterize
pituitary-gonadal function. Twelve years later, we were able to locate 17 of the patients, and 16 of these agreed
to participate in a questionnaire-based follow-up study. Follow-up data about the other patients were gleaned from
available medical records as were corroborative data regarding the 16 study participants. Our results indicate
that this form of early puberty is a benign entity. Seventy percent of our patients experienced cessation of their
early pubertal development, whereas the remainder reported a slowly progressive course. Those with a slowly progressive
course were older than those with an unsustained course [mean age of the larche, 6.1 vs. 3.4 yr (P < 0.01);
age of pubarche, 6.0 vs. 4.0 yr (P = 0.02); age at our evaluation, 7.1 vs. 5.2 yr (P = 0.02)]. They also had more
advanced skeletal maturation (bone age, 10.2 vs. 7.3 yr; P = 0.04) at the time of our evaluation. Both groups,
however, had similar outcomes with respect to linear growth and young adult reproductive function. On the average,
the study patients reached their genetic targets for final height (mean final height, 165.5 +/- 2.2 cm; mean genetic
target height, 164.0 +/- 1.1 cm; P = NS). The average age of menarche was 11.0 +/- 0.4 yr. Twenty-three percent
of our patients have evidence of anovulatory menstrual cycles, which is comparable to the 28% found in normative
studies of similarly aged women. Two of the patients have become pregnant to date. Unsustained or slowly progressive
puberty in young girls does not warrant therapy with GnRH agonists. Thus, when evaluating patients with early pubertal
development, one should ensure that sexual maturation is continually progressive before initiating potentially
unnecessary therapy.
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