Gian Filippo Rondanini

Congenital hypothyroidism: Auxological retrospective study during the first six years of age

We examined length, height and weight from birth to six years of age and head circumference during the first two years in 89 children with congenital hypothyroidism (CH). The patients were divided in two groups: children diagnosed by clinical criteria during the first year of life (group A) and children detected by neonatal screening (group B). Group A showed a complete catch up growth for height and weight 10 months after the beginning of the replacement therapy; to the contrary, group B did not show any difference for height and weight compared to normal standards. Head circumference, evaluated only in group B, was significantly higher in comparison with normal standards. When etiology of CH was taken into consideration, children with athyreosis showed a significantly lower length at birth and at three months of age and their growths curves normalized after institution of replacement therapy. In conclusion our data suggest a direct relationship between severity and duration of hormone deficiency and growth retardation and confirm that replacement therapy started within the first year of live in CH patients clinically diagnosed allows a catch up growth.

Neurophysiologic Studies and Cognitive Function in Congenital Hypothyroid Children

ABSTRACT: Minor neurologic and intellectual impairments have been described in some congenital hypothyroid (CH) children in spite of early detection by neonatal screening. The aim of our study was to assess cognitive functions as well as neurophysiologic parameters in hypothyroid children and to compare children detected by neonatal screening (group A) versus hypothyroid patients clinically diagnosed before the beginning of the screening program (group B). Group A consisted of 15 children (13 girls, mean age at the beginning of treatment 33 d). Group B consisted of 11 patients (7 girls, mean age at the start of treatment 10.1 mo). Twenty age-matched healthy children were studied as a control group for neurophysiologic tests. Neurophysiologic tests (Auditory P 300, long latency somatosensory evoked potentials (LL-SEP) were performed along with IQ evaluation. Abnormalities of neurophysiologic tests were detected in 82% of clinically diagnosed hypothyroid children. Surprisingly, 47% of the children detected by neonatal screening, having normal mental development index, showed at least one abnormal neurophysiologic test. LL-SEP latencies were found significantly increased in both groups of CH patients compared with controls. Our data are suggestive for a prenatal or perinatal CNS damage in some children with congenital hypothyroidism, despite early treatment.

HLA genotypes and HLA-linked genetic markers in Italian patients with classical 21-hydroxylase deficiency

SummaryHLA genotype and HLA-linked marker data for 40 unrelated patients from central Italy and 2 unrelated patients from Sardinia with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH-def) were analyzed. The results confirm that the HLA-linked 21-OH-def gene is associated with several different HLA determinants and complete HLA haplotypes, although the only determinant with significantly increased frequency was the complement C2 allele C2B. The HLA antigens B8 and DR3 were found in significantly decreased frequencies. The haplotype A3, Cw6, Bw47, BfF, DR7, which is exceptionally rare in the general population but which has been found in many other 21-OH-def patients from diverse geographical origins, was also found in one of the Italian patients. This and other HLA haplotype associations found among the Italian patients may represent mutations that have occurred on HLA haplotypes with genetic linkage disequilibrium or, alternatively, may represent mutations that have not yet had time to become randomly associated with different HLA complex determinants. The marked negative associations with B8 and DR3 could, however, result from an interaction between the gene products of the HLA complex and the 21-OH-def phenotype.

Pancreatic Endocrine Function in Leukemic Children Treated with L-Asparaginase

The effect of arginine infusion on blood glucose and plasma levels of insulin, C-peptide and glucagon has been studied in leukemic children before and after treatment with L-asparaginase (10,000 U/m2/day for 10 days). Therapy induced a significant reduction in basal and peak blood glucose, insulin and C-peptide levels, while glucagon was unmodified. The conserved C-peptide-insulin molar ratio suggests the interference of L-asparaginase with proinsulin synthesis. In conclusion our results prove a decreased insulin reserve with a preserved, although reduced, beta-cell function.

Genotyping for 21-hydroxylase deficiency: one or two genes?

We have devised nomograms relating the baseline and ACTH stimulable levels of 17-OHP, Δ 4-androstenedione and testosterone for genotyping 21-hydroxylase deficiency. The nomograms provide a method for classifying the patient with congenital, late onset or cryptic 21-hydroxylase deficiency as well as classifying the heterozygotes for each of these disorders. In addition, the subject predicted by HLA genotyping to be genetically unaffected can also be classified by these nomograms. Further the nomograms permit us to obtain evidence for genetic recombination between HLA and the 21-hydroxylase locus. For example a patient predicted by initial HLA genotyping to be unaffected was classified by the nomogram to be a heterozygote. When HLA-DR typing was performed an informative maternal HLA A:DR recombination was discovered. This recombination explained the heterozygote response of this subject. In another family a maternal DR:GLO recombination was found in an asymptomatic sister who was HLA identical to the patient with late onset 21-hydroxylase deficiency. Although most recombinants have mapped the gene for 21-hydroxylase between B and DR, this DR:GLO recombination presents evidence that there may also be a 21-hydroxylase locus between the DR-GLO loci. The nomograms thus provide a powerful tool to determine the 21-hydroxylase genotype by hormonal testing and assist in mapping the gene for 21-hydroxylase deficiency.

Biochemical evidence of 21-OH deficiency without clinical symptoms in two family members of a CAH-affected child

HLA typing was performed in a family with a child affected by salt-wasting CAH due to 21-OH deficiency. Father,mother, sister were clinically normal, with absence of signs of virilization or salt-wasting symptoms, normal stature and fertility. Based on the linkage of the gene for 21-OH deficiency to the HLA complex, the sister resulted heterozygous for the gene of CAH:Three heterozygous members were therefore found in this family: father,mother,sister. Heterozygous carriers of the CAH-gene are expected to have normal baseline hormone levels.On the contrary father and sister were found to have abnormally elevated hormone levels, even if clinically normal.Both have the CAH gene-linked haplotype (“a” in father, “c” in sister) and the “b” haplotype. It is speculated that the biochemical abnormalities in absence of clinical signs are the result of the combination of a gene for a mild 21-OH defect (linked to the “b” haplotype) with the gene for the severe 21-OH defect (linked to “a” and “c” haplotype).

Late-Onset, Cryptic and Classical 21-OH Deficiency: Allelic Variants

HLA genotyping and hormonal studies in 9 females with non-classical steroid 21-hydroxylase deficiency (AAH) indicate that this disorder is due to an autosomal recessive gene linked to HLA, similar to classical and cryptic 21-hydroxylase deficiency (21-OH def). They had normal genitalia at birth and presented between 9 mos to 16 yrs with varying degrees of virilization. Hormonal studies of the families revealed 2 fathers and their HLA identical sisters with 21-OH def. The remaining parents and the sibs sharing one HLA haplotype with the AAH patient responded to ACTH stimulation as heterozygotes for classical or cryptic 21-OH def. Five sibs who were HLA identical to their affected sib also had findings diagnostic of 21-OH def. The hormonal response to ACTH of the patients with AAH and their HLA identical sibs was similar to that of patients with cryptic 21-OH def. Thus, individuals with these non-classical forms of 21-OH def and similar hormonal findings present with a clinical spectrum ranging from an asymptomatic deficiency to precocious pubic hair, acne, tall stature and advanced bone age, hirsutism, clitoromegaly and menstrual irregularities. The results of these studies support the concept that AAH, similar to classical and cryptic 21-OH def is due to an HLA linked autosomal recessive gene and that these disorders are due to allelic variants at the locus of steroid 21-hydroxylase.

Linkage between HLA antigens and obesity.

We performed HLA typing in 122 obese children, 47 with a history of familial obesity and 75 with a negative history. The control group consisted of 905 subjects, without family relation with patients, living in the same geographical area. Our results show: 1)in the 47 patients with familial obesity a significant increase in HLA B13 antigen as compared to controls (p <.05), with a relative risk of 3.45; 2)in the 75 patients without a history of familial obesity a significant fall in HLA A2 antigen (p <.03) as compared to controls. 3)All obese patients evidenced a highly significant increase in HLA -A and -B blanks as compared to controls, the increase being higher for locus A (chi square=47.83, p<<.0001) than for locus B (chi square=9.20, p <.003). This seems to support the hypothesis that at least in a number of patients hereditary predisposition plays an important role in the aetiology of obesity and to indicate that such predisposition involves genes controlled by the HLA chromosomic region. The higher frequency of blanks in obese subjects might be connected with a diminished phenotypic expression of HLA antigens or with the presence in the serum of obese patients of a HLA antigens masking factor.