Ana Keselman

Growth Follow-up in 100 Children with Congenital Hypothyroidism Before and During Treatment

In order to assess the influence of age at onset of treatment on subsequent growth, height, weight, head circumference (HC) and bone age as estimated by Greulich-Pyle and TW2-RUS methods, 100 children with congenital hypothyroidism (CH) were studied before and during adequate treatment up to 5 years of age. The patients were divided into five groups according to age at the start of treatment: Group 1: < 2 months (n = 26); Group 2: 2-3 months (n = 13); Group 3: 3-6 months (n = 21); Group 4: 6-12 months (n = 20); Group 5: 12-24 months (n = 20). Before treatment, groups 1 and 2 differed significantly from the others in height (p < 0.001). With hormone therapy, catch-up growth was observed in groups 3 to 5, but at age 5 years no differences were found between groups. In all groups, height at 5 years of age correlated significantly with childrens midparental height (p < 0.002). Bone age was initially retarded in groups 3 to 5, but approximated the chronological age by age 5 years. Initially, HC was less affected than height and remained relatively larger up to age 5 years in all groups. These findings show that thyroid hormone replacement in CH as late as 24 months corrects the short stature and delayed bone age by age 5 years.

Heterozygous IGFALS Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

Background: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. Patients and Methods: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. Results: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. Conclusions: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

CONTEXT Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. OBJECTIVE We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. DESIGN AND SETTING We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. PATIENTS AND METHODS A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. RESULTS Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. CONCLUSIONS Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

Psychosocial outcome in growth hormone deficient patients diagnosed during childhood.

Social disabilities have been described in GHD patients. The aim of this study was to evaluate the social outcome of a group of adult hypopituitary patients diagnosed and treated during childhood. Seventy patients were interviewed at a mean age of 25.6 years (range 18-50 yr). They answered a semistructured questionnaire and the Beck Depression Inventory test. Patients were compared for academic achievement, marital status and employment with the nearest age sibling. We found high levels of school repeaters, school was often not completed, and around 50% were overprotected by teachers and teased by peers. 32% were unemployed, while 58% of those employed work with their families. 80% still live with their parents; only 16% are married and 9% have children. 44% had no dating experience and 52% had never had sexual intercourse. Depression was common, especially in hypogonadic subjects. Juvenilization was the most common complaint. We did not found differences in maximal educational achievements and levels of employment between patients and siblings, but significantly more married siblings were found. Depression, social isolation and dependent life style were found in GHD patients. Appropriate medical and psychological counseling should be included for patients and their families as part of treatment.

Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11

INTRODUCTION: Around 50% of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene. AIM: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation. PATIENTS: 33 NS patients (23 males). METHODS: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced. RESULTS: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85%), short stature (79%), webbed neck (77%) and cryptorchidism (60%) in boys. The mean height SDS was -2.7 ± 1.2 and BMI SDS was -1 ± 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38% vs. 6%, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS. CONCLUSION: We identified missense mutations in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.

Neonatal cholestasis in congenital pituitary hormone deficiency and isolated hypocortisolism: characterization of liver dysfunction and follow-up

INTRODUCTION Neonatal cholestasis due to endocrine diseases is infrequent and poorly recognized. Referral to the pediatric endocrinologist is delayed. OBJECTIVE We characterized cholestasis in infants with congenital pituitary hormone deficiencies (CPHD), and its resolution after hormone replacement therapy (HRT). SUBJECTS AND METHODS Sixteen patients (12 males) were included; eleven with CPHD, and five with isolated central hypocortisolism. RESULTS Onset of cholestasis occurred at a median age of 18 days of life (range 2-120). Ten and nine patients had elevated transaminases and γGT, respectively. Referral to the endocrinologist occurred at 32 days (range 1 - 72). Remission of cholestasis occurred at a median age of 65 days, whereas liver enzymes occurred at 90 days. In our cohort isolated, hypocortisolism was a transient disorder. CONCLUSION Cholestasis due to hormonal deficiencies completely resolved upon introduction of HRT. Isolated hypocortisolism may be a transient cause of cholestasis that needs to be re-evaluated after remission of cholestasis.

Tratamiento con hormona de crecimiento en niños menores de 6 años de edad, con talla baja, nacidos pequeños para la edad gestacional

INTRODUCTION Approximately 10% of children born small for gestational age (SGA) do not show spontaneous catch-up growth. OBJECTIVE Our objective was to assess the efficacy and safety of 2 years growth hormone treatment in children younger than 6 years of age, born SGA. MATERIAL AND METHODS Fourteen patients, mean age 4.2 + or - 1.1 years were treated with growth hormone at 1.0 UI/kg/wk for two years. RESULTS Growth velocity increased from a mean + or - SD of 5.4 + or - 1.7 cm/yr to 9.8 + or - 1.50 cm/yr and 7.6 + or - 1.5 cm/yr during the first year and second year, respectively (p 0.00058). Serum IGF-I and its binding protein BP3 increased significantly throughout treatment. Basal glucose and insulin levels increased significantly during treatment, p= 0.0006 and p= 0.036, respectively, without significant changes in postprandial glucose or insulin levels. A mild change in insulin sensitivity was observed along treatment. CONCLUSION Two years growth hormone treatment induced a significant growth acceleration in children born small for gestational age, allowing them to attain a normal height. No serious adverse events were reported.

Hypogonadotropic Hypogonadism in Infants with Congenital Hypopituitarism: A Challenge to Diagnose at an Early Stage.

Background: Combined pituitary hormone deficiency (CPHD) presents a wide spectrum of pituitary gland disorders. The postnatal gonadotropic surge provides a useful period to explore the gonadotropic axis for assessing the presence of congenital hypogonadotropic hypogonadism (CHH). Aim: To explore the functioning of the hypothalamic-pituitary-gonadal axis in the postnatal gonadotropic surge for an early diagnosis of CHH in newborns or infants suspected of having CPHD. Subjects and Methods: A cohort of 27 boys under 6 months and 19 girls under 24 months of age with suspected hypopituitarism was studied. Serum concentrations of LH, FSH, testosterone, inhibin B, anti-Müllerian hormone (AMH) and estradiol were measured, and male external genitalia were characterized as normal or abnormal (micropenis, microorchidism and/or cryptorchidism). Results: CPHD was confirmed in 36 out of 46 patients. Low LH and testosterone levels were found in 66% of the hypopituitary males, in significant association with the presence of abnormal external genitalia. This abnormality had a positive predictive value of 93% for CHH. No significant association was observed between serum FSH, AMH and inhibin B and the patients external genitalia. Conclusion: In newborn or infant boys with CPHD, LH and testosterone concentrations measured throughout the postnatal gonadotropic surge, together with a detailed evaluation of the external genital phenotype, facilitate the diagnosis of CHH at an early stage.

Association of serum components of the GH-IGFs-IGFBPs system with GHR-exon 3 polymorphism in normal and idiopathic short stature children

OBJECTIVE To investigate the possible association of circulating components of GH-IGFs-IGFBPs system with the GHR-exon 3 genotype in normal and idiopathic short stature (ISS) children. DESIGN Descriptive, cross-sectional study in normal and ISS children. SUBJECTS AND METHODS 192 normal and 81 ISS children (age: 5-17 years) were included. Serum IGF-I, IGFBP3, ALS and GHBP levels were measured. GHR-exon 3 polymorphism (GHRd3) was analyzed by multiplex PCR assay. Normal and ISS children were divided according to GHR-exon 3 genotype: homozygous for the full-length GHR isoform (GHRfl) and carriers of one or two copies of the GHRd3 allele. RESULTS GHRd3 genotype distribution (fl:fl/fl:d3/d3:d3,%) in normal (60:34:6) and ISS (64:32:4) was similar and reached Hardy-Weinberg equilibrium. ISS children had significantly reduced levels of GHBP and GH-dependent factors as compared to controls (p<0.0001). Within the normal group, homozygous carriers of the GHRfl allele had significantly higher GHBP serum levels than those with one or two copies of the GHRd3 allele (Mean ± SEM; GHRfl: 3.2 ± 0.2 vs GHRd3: 2.7 ± 0.2 nmol/L, p = 0.04). No other significant association with GHR exon 3 polymorphism was found in either the normal or the ISS groups. CONCLUSIONS GHR exon 3 polymorphism is distributed similarly in normal and ISS children, however only normal homozygous children for GHRfl allele showed higher GHBP levels. The lack of association between GHBP and GHR polymorphism in ISS children might be related to the heterogeneity of this group, where potential defects in GH receptor action may result in partial GH insensitivity.

Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency

Acid‐labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF‐I and IGFBP‐3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families.