Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism.

AIM: Leprechaunism, a rare genetic disease resulting from mutations in two alleles of the insulin receptor gene, is characterized by severe insulin resistance, retarded growth and, usually, premature death. The ability of treatment with recombinant human insulin-like growth factor 1 (rhIGF1) to improve metabolic and clinical parameters in the long-term is still controversial. METHODS: Mutations were looked for in the insulin receptor gene of a four-month-old female baby with leprechaunism. The patient's skin fibroblasts were analyzed for response to insulin and IGF1. At the clinical level, the very long-term effects of treatment with rhIGF1/rhIGFBP3 were evaluated by clinical and metabolic parameters. RESULTS: The patient's diagnosis was based on compound heterozygous mutations in two alleles of the insulin receptor gene, thus confirming leprechaunism. Cultured fibroblasts showed a decreased number of insulin receptors and were insulin-resistant. However, IGF1 was able to stimulate IGF1 receptor signalling, suggesting possible activation of a salvage pathway. Treatment with IGF1/IGFBP3 for 8.7 years, then IGF1 for 2 years, resulted in normalization of circulating levels of IGF1 and IGFBP3. Large daily variations in glycaemia and insulinaemia persisted, but mean glycaemia decreased. Regarding growth, the patient's BMI Z score normalized and length/height score improved. Our patient presented normal neurological development and academic achievement. The treatment was free of adverse effects. CONCLUSION: Our results provide evidence that rhIGF1 with and without rhIGFBP3 can prevent fatal outcomes, and improve growth and metabolic parameters, for more than 10 years in a patient with leprechaunism. Long-term rhIGF1 for severe insulin resistance syndrome should be considered.

Treatment of an infantile acne with oral isotretinoin.

We report the case of a little girl who presented with a nodulocystic acne which had its onset at the age of 20 months. She had no clinical or biological features of endocrinopathy. The lesions did not respond to conventional antibiotics so she was started on oral isotretinoin. A seven-month treatment period was necessary to achieve remission. The onset of infantile acne is usually around 6 to 16 months and there is a male predominance. The onset is later in females. Oral erythromycin is the first line treatment when topical therapies are inefficacious. Some cystic lesions do not respond to oral antibiotics. In these cases, oral isotretinoin may be effective and the treatment is similar to that of an adult. Clinical and biological tolerance is good with no growth retardation. Lesions may relapse after the withdrawal of isotretinoin but they are less important and easily controlled with topical treatments. Isotretinoin can be used for nodulocystic acne to reduce the risk of scarring.

True hermaphroditism: genetic variants and clinical management.

The diagnosis and management of 22 patients with true hermaphroditism are described. Sixteen of them were first seen before the age of 4 months. The initial manifestations were ambiguous genitalia in 20 cases (two of them identified prenatally by ultrasound examination), isolated clitoromegaly in one, and penile hypospadias plus unilateral cryptorchidism in one. All patients but one had at least one palpable gonad. Eleven of the twelve patients examined before the age of 6 months had basal plasma testosterone levels > 0.4 ng/ml. In older patients the stimulation test was necessary to demonstrate male testosterone secretion. The most common peripheral karyotype was 46,XX (17 cases); the other karyotypes were 47,XXY (1 case) and mosaicism 46,XX/46,XY (2 cases) or 46,XX/47,XXY (2 cases). One of the patients with the 46,XX karyotype had 46,XX/46,XY on fibroblast culture; four had the SRY gene in their leukocytes and one in the tissue taken at gonadal biopsy. A vagina was found in all patients at laparotomy, and a uterus was found in 17 cases (as a hemiuterus in 9). Genitography failed to demonstrate a uterus in only one case. The testicular tissue was dysgenetic but the ovarian tissue was normal. Sex assignment was male in 8 patients (reoriented by us in 2) and female in 14 patients (reoriented by us in 3). Spontaneous pubertal development occurred in the 4 patients (2 boys, 2 girls) with gonadal tissue who reached pubertal age. We conclude that true hermaphroditism is a heterogeneous condition in terms of its genetic background, with a prevalence of the 46,XX karyotype. There may be mosaicism with a Y-bearing cell line limited to the gonad (its frequency is probably underestimated), a paternal meiotic exchange between X and Y occurring in 46,XX cases with SRY, or a lack of the SRY gene, suggesting that other genes working independently of SRY may also determine testicular differentiation.

Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy.

We studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 +/- 9.0 ng/mL, 1.1 +/- 0.2 microgram/mL, and 7.6 +/- 3.3% of radioactivity as compared to time 0 values: 13%%o/- 15 ng/mL, 2.2 +/- 0.2 micrograms/mL, and 20.0 +/- 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months, suggesting suboptimal nutrition during this period. Six months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient we observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients.

[Clinical aspects of gonadal dysgenesis]. / Aspects cliniques des dysgénésies gonadiques.

Gonadal dysgenesis are classified according to the aspect of external genitalia. The group with female genitalia includes Turner's syndrome, and "pure" dysgenesis; the group with male genitalia involves Klinefelter's syndrome, XX males and may be anorchia; the group with ambiguous genitalia includes "mixed" gonadal dysgenesis, true hermaphroditism and Leydig-cell agenesis. An algorythmic approach to patients with ambiguous external genitalia is presented in order to distinguish between gonadal dysgenesis and male or female pseudohermaphroditism.

[Esophageal pH measurements in newborn infants. Value and indications]. / pH métrie oesophagienne chez le nouveau-né. Intérêts et indications.

Esophageal pH monitoring is now the most reliable test in the diagnosis of gastroesophageal reflux (GER) in infants and children. A 18-24 hr esophageal pH monitoring is undertaken in 26 newborns to validate this test for this age group where GER is frequent with fair correlation of clinical presentation. In 19 infants with suspicion of GER, this test give a positive diagnosis in 12 of them. Seven out of these 12 infants have another investigations (barium- esophagram - scintigraphy - esophagoscopy) with only a positive diagnosis of GER in 4 cases. Esophageal pH monitoring in 7 control infants show that the percent of monitoring time with pH below 4.0 is one of the best discriminative values (upper limit: 4.2%) for the diagnosis of GER. Unusual symptoms of GER in the neonatal period as apneic spells, dyspnea, cyanosis or neurological signs are indications for esophageal pH monitoring.