Genetic IGF1R defects: new cases expand the spectrum of clinical features.

PURPOSE: We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade. PATIENTS AND METHODS: Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available. RESULTS: A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism. CONCLUSION: We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.

Acquired resistance to pamidronate treated effectively with zoledronate in juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare autosomal recessive osteopathy. There is still a question about the most effective treatment modality in long-term prognosis. A 9-month-old boy who suffered from bone pain and deformities with a very high alkaline phosphatase level was diagnosed as JPD by radiographic findings. Genetic analysis showed a homozygous large deletion in TNFRSF11B gene encoding osteoprotegerin. Clinical improvement was observed with intravenous pamidronate therapy. However, the effect of drug reduced in time so the annual dose per kilogram body weight was increased after 2 years. Despite this increment, bone fractures developed and bone pain recurred with high-ALP levels, which suggested resistance to pamidronate. Switching to zoledronate resulted a significant improvement in bone findings radiographically and ALP level. Severe hypocalcemia requiring intravenous calcium treatment complicated the first dose of zoledronate, but not recurred thereafter. Intravenous pamidronate therapy is effective in reducing bone pain, improving bone deformities and motor development in infantile onset JPD. However, this effect can be transient. Switching to another bisphosphonate like zoledronate may provide long-term clinical and biochemical improvement as an alternative treatment in case of resistance to pamidronate therapy.

Assessment of thyroid function during the long course of Hashimoto's thyroiditis in children and adolescents.

CONTEXT: The prognosis of Hashimoto's thyroiditis (HT) in children and adolescents is not well known and studies reporting long-term outcome of the disease are scarce. OBJECTIVE: To assess the thyroid hormone status during long-term follow-up and to establish the prognosis of children and adolescents with HT. PATIENTS: One hundred and twenty-nine patients with HT were re-evaluated for thyroid hormone status after a mean follow-up period of 50 months. RESULTS: Seventy-seven per cent of the euthyroid patients were still euthyroid, while 21.1% of these patients became hypothyroid at the time of re-evaluation. However, 69.5% of hypothyroid patients remained hypothyroid (overt or subclinical) and 30.5% recovered. CONCLUSION: HT is a dynamic process. Thyroid functions can show variation during follow-up. Therefore, thyroid function tests should be repeated periodically to detect progression to hypothyroidism in initially euthyroid patients as well as reversibility of hypothyroidism.

Hashimoto's thyroiditis in children and adolescents: a retrospective study on clinical, epidemiological and laboratory properties of the disease.

UNLABELLED: Hashimoto's thyroiditis (HT) is the most common cause of goiter and acquired hypothyroidism in children and adolescents in iodine replete areas. To find out the clinical, epidemiological and laboratory characteristics of the disease in childhood, we reviewed files of 162 children and adolescents with HT followed in the Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine. RESULTS: Female patients constituted 86.4% (n = 140) of all patients with a female:male ratio of 6.4. Mean age at diagnosis was 11.4 +/- 2.97 years (age range 4.4-16.5 years). At the time of diagnosis 43.2% of the patients (n = 70) were euthyroid, 24.1% (n = 39) had subclinical hypothyroidism, 21% (n = 34) had overt hypothyroidism, and 8.6% (n = 14) had overt and 3.1% (n = 5) subclinical hyperthyroidism. CONCLUSIONS: Autoimmune thyroiditis is more frequent in females, and increases in frequency over age during childhood and adolescence. At the time of diagnosis, frequency of overt and subclinical hypothyroidism is similar to that of euthyroid goiter.

Comparison of stimulated growth hormone levels in primed versus unprimed provocative tests. Effect of various testosterone doses on growth hormone levels.

OBJECTIVE: To show the importance of priming prior to growth hormone (GH) stimulation tests in the diagnosis of GH deficiency, the effect of different doses and schedules of testosterone (T) on GH levels. PATIENTS AND METHODS: Eighty-four prepubertal and early pubertal boys whose heights were 2 SD below the mean and height velocities <4 cm per year and who failed in GH stimulation tests were included in the study. The boys were divided into two groups: the first group consisting of 41 boys was primed with 62.5 mg/m(2) (low dose testosterone - LDT) and the second group consisting of 43 boys with 125 mg/m(2) depot testosterone (conventional dose testosterone - CDT) intramuscularly 1 week before the stimulation test. Twenty-one boys out of 36 who failed in GH stimulation tests after one dose T injection were treated with three doses of 62.5 mg/m(2) T (multiple dose testosterone - MDT) injections monthly and retested. RESULTS: The GH levels increased from 4.80 +/- 2.78 to 11.50 +/- 8.84 ng/ml and from 4.76 +/- 2.46 to 12.98 +/- 8.30 ng/ml by priming with LDT and CDT respectively. The increment of mean GH levels by both LDT and CDT were found to be similar (p = 0.443). The peak GH levels were found to be elevated >10 ng/ml in 22/41 (54%) and 26/43 (60%) who received LDT and CDT respectively (p = 0.528). The mean GH level of 21 boys who received MDT was increased from 5.38 +/- 2.50 ng/ml (by priming with one dose T) to 10.19 +/- 6.13 ng/ml (p = 0.004). Twelve (57%) of 21 boys who received MDT responded to GH stimulation test >10 ng/ml. The T level increased from 0.71 +/- 0.97 to 4.54 +/- 2.80 ng/ml by LDT (p < 0.001) and from 0.65 +/- 0.71 to 7.18 +/- 3.18 ng/ml by CDT (p < 0.001). The increment of T level was higher by CDT than LDT (p = 0.001). There was no correlation between T and peak GH levels after priming. CONCLUSION: LDT is as effective as CDT in priming of GH stimulation tests. The ones who failed in GH stimulation tests after one dose T injection can be primed with MDT. The stimulated GH level after priming was related neither to the plasma level of T nor the dose of T.

Severe lymphopenia in tuberculosis. A mere coincidence or a significant association?

A variety of infectious agents can cause secondary immunodeficient states. We herein present a one-year-old patient, admitted to the hospital with severe lymphopenia, who was subsequently diagnosed as tuberculosis. After the antituberculosis (anti TB) therapy was started, the clinical condition and the immunologic findings of the patient improved. We have thus concluded that the transient lymphopenia of the patient was due to Mycobacterium tuberculosis. We suggest that immunodeficiency should be investigated more often in children with tuberculosis and that further studies will shed light on the pathogenesis of this aspect of the disease.

Periorbital cellulitis: a comparison of different treatment regimens.

Periorbital cellulitis was retrospectively investigated in a cohort of 69 children, 1.5-16 years of age, who were admitted to Hacettepe University Children's Hospital. The aim of the study was to define the most important cause of the disease and to choose the most appropriate antimicrobial regimen. Sinusitis (43%) was found to be the most frequent disease associated with periorbital cellulitis. Trauma (25%) and odontogenic infections (6%) were the next most common predisposing causes. Staphylococcus aureus was isolated from 14 (74%) of 19 cultures. Two antibiotic combinations, penicillin plus chloramphenicol and sulbactam-ampicillin (SAM) with or without ornidazole was used in 30 (43%) and 39 (57%) of 69 cases, respectively. The duration of treatment with these two antibiotic combinations was generally between 7 and 10 days. No statistical difference was found between the two antibiotic combinations in the cure and recurrence rates but five (17%) of the 30 cases using penicillin plus chloramphenicol, and one (3%) of the 39 cases using SAM with or without ornidazole had recurrent periorbital cellulitis. It was concluded that SAM can be the first line of drug treatment for periorbital cellulitis as it is easily used in every age group and etiology (trauma, sinusitis, etc.). It provides total recovery and has less side effects and risk of recurrence. It also has a broad antimicrobial spectrum.