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.

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.

[Thrombocytosis and neonatal subcutaneous adiponecrosis]. / Trombocitosi e adiponecrosi sottocutanea neonatale.

The authors report three newborns with subcutaneous fat necrosis, that appeared between the 4th and 21st day of life. The infants, full term of normal weight, presented severe perinatal hypoxia and needed primary resuscitation. Severity and duration of perinatal hypoxia were not related with the time of cutaneous lesion onset. Serum calcium levels were in the higher values of the neonatal normal range. Vitamin D levels were within the normal range and only one patient showed a transient elevation of PTH, suggesting a poor relevance of both these factors in determining serum calcium increase. All patients showed a marked increase of platelets number, before the onset of clinical manifestations. Thrombocytosis could play an important role in the pathogenesis of adipose tissue necrosis, causing lower blood perfusion with relative hypoxia and hypothermia.

Encephalocraniocutaneous lipomatosis: case report and review of the literature.

Encephalocraniocutaneous lipomatosis is a congenital disorder characterized by unilateral cerebral malformations and ipsilateral scalp, face, and eye lesions. Distinguishing histopathologic features are dysgenesis and neoplasia of the adipose tissue. A Caucasian boy had soft tumors and elastic papules on his head since birth, associated with atrophic areas, and a bilobed lesion on the upper right eyelid. On the bulbar conjunctiva of the right eye, an oval 6-mm lesion was present. Ultrasonogram, computerized tomographic scan, and magnetic resonance imaging revealed a dilation of the right lateral ventriculus, a mass on the pontocerebellar angle, agenesia of the corpus callosum, an arachnoidal cyst on the right hemisphere, microcalcifications, and pachygyria. The histology of a soft cutaneous tumor was consistent with a fibrolipoma, and dispersed extracellular lipid globules in the upper dermis were found on electron microscopy. The diagnosis suggested by these findings was encephalocraniocutaneous lipomatosis. Even in view of the rarity of the syndrome (11 cases described in the literature), this patient seems unusual because of the bilateral distribution of the cutaneous lesions and because of the agenesia of the corpus callosum. The peculiar ultrastructural findings require further confirmation.

Congenital hypothyroidism and pericardial effusion.

A group of infants, affected by congenital hypothyroidism diagnosed through the neonatal screening program, was investigated with echocardiography to detect the presence of pericardial effusion. We studied the relationship between the effusion and the etiology of hypothyroidism, established through thyroid scintiscanning. Our data show a high prevalence of effusion in hypothyroid patients, without other clinical signs of cardiac involvement as well as a relationship between the etiology of hypothyroidism and the presence of effusion. This seems to be much more frequent in those forms which can imply a more severe hormonal defect, particularly during fetal life (agenesis/dyshormonogenesis). Furthermore, the high prevalence of pericardial effusion suggests to start the L-T4 replacement therapy with lower dosages as commonly advised, in order to avoid a cardiac involvement.

[Screening for obesity in a schoolchildren population of the 20th zone of Milan and a nutritional education intervention]. / Screening dell'obesità nella popolazione scolastica della zona 20 di Milano ed intervento di educazione alimentare.

Our study was performed in 1986-'87 and 1987-'88 school years on 12.354 three to eighteen years old students (the whole scholastic population of zone 20 of Milan) in order to apply dietary education on obese subjects. Mean prevalence of obesity was 13.4% with elevated percentages in 11 to 13 years old students (17.9%), with respect to primary (14.1%), high school (12.4%) and nursery school (4.7%). The 36% of obese subjects (more than 50% of adolescents) had already tempted to reduce body weight. Intervention reduced % weight excess (from 33.6 +/- 0.5% to, 28.8 +/- 0.5% after 12 months, p less than 0.001); 67% of obese subjects lost weight and body weight returned within normal limits in 31% of subjects. An educational dietetic strategy may be successful in childhood obesity.

Free thyroid hormones in evaluating persistently elevated thyrotropin levels in children with congenital hypothyroidism on replacement therapy.

Some children with congenital hypothyroidism receiving L-T4 therapy have elevated serum TSH levels despite having normal serum T4 concentrations, suggesting that they have a higher threshold for the feedback regulation of TSH release. To further study this possibility, we determined serum free T4 (FT4) and T3 (FT3) concentrations in two groups of L-T4-treated hypothyroid children. Group A consisted of 10 patients with high serum TSH levels; group B consisted of 10 patients with normal TSH levels. All patients were clinically euthyroid, and serum total T4 and T3 concentrations were similar in the two groups. A third (control) group (C) consisted of randomly selected normal children. The three groups were age matched. Serum FT3 and FT4 were significantly lower in group A compared to group B. Serum FT4 and T4 were higher and TSH was lower in group B compared to group C. The T4/T3 ratio wash higher in both groups of children with hypothyroidism than in group C. We conclude that in most patients a high serum TSH was due to inadequate L-T4 therapy, as shown by free hormone concentrations (low) but not by total hormone levels (normal). This suggests that L-T4 therapy should be monitored by measurement of TSH and free hormone concentrations. The latter also can be used to indicate moderate overdosage, not clinically detectable, as shown by the comparison between groups B and C. Measurement of serum total T4, as indicated by the lack of difference between groups A and B and also by T4/T3 ratio, cannot be considered a reliable index of therapeutic adequacy in such children.

[Hormonal therapy of congenital hypothyroidism in childhood]. / La terapia ormonale dell'ipotiroidismo congenito in età infantile.

L-tiroxine (L-T4) substitutive therapy has been evaluated in a group of 15 hypothyroid children (6 males and 9 females), one to six years old. We have found a wide dosage range, being not possible to find any significant difference between ranges leading to normal and ranges leading to pathological findings, thus making impossible to suggest a reasonably safe dosage pro kg. of body weight. Increasing L-T4 dosage we have got a significant increase of FT4 levels, a significant decrease of TSH levels, but no variations of FT3 values, indicating an individual capability in regulating FT3 disposal. FT3 and TSH are the most valuable indexes of therapy adequacy, since their normality reflects an euthyroid status; we should achieve an individually adequate dose of L-T4, based on clinical judgment and hormonal findings.

[Follow-up and prognosis of congenital hypothyroidism]. / Follow-up e prognosi dell'ipotiroidismo congenito.

Neonatal screening of congenital hypothyroidism has been recently extended to the most of North America, Australia, Europe, and to several Italian areas. Before screening programs, several Authors reported neurological defects and behavioral disturbances also in patients whose treatment has been precocious, thus stressing the importance of an antenatal thyroidal defect. We have therefore setted up a follow-up program to evaluate the prevalence and to treat such disturbances in hypothyroid children. In this report we describe the program, present the most significant preliminary data and discuss the prognosis of hypothyroid patients detected by screening programs.

Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia.

Hormonal studies and human leukocyte antigen (HLA) genotyping were performed in 5 males and 13 females who were demonstrated to have 21-hydroxylase deficiency. The enzymatic deficiency of steroidogenesis was detected by family studies of 10 females who presented with varying symptoms of androgen excess. The 10 index cases had normal genitalia at birth, but virilized to varying degrees postnatally. The additional 8 affected family members had not sought medical care, but some were found to have signs of virilization on physical examination, while others were normal. Thus both late-onset (symptomatic) and cryptic asymptomatic) 21-hydroxylase deficiency occurred in the same pedigree. The hormonal and genetic linkage studies indicate that the late-onset (symptomatic) form of 21-hydroxylase deficiency, like the cryptic (asymptomatic) and classical forms of 21-hydroxylase deficiency, is transmitted by an autosomal recessive gene which is linked to HLA-B. Furthermore, the classical form of 21-hydroxylase deficiency associated with prenatal virilization is transmitted by an allelic variant for steroid 21-hydroxylase different from that of the nonclassical forms, late-onset (symptomatic) and cryptic (asymptomatic) 21-hydroxylase deficiency. Although these latter 2 disorders have different clinical manifestations, they demonstrate a similar degree of steroid 21-hydroxylase deficiency that is less severe than that observed in classical 21-hydroxylase deficiency. The hormonal and genetic linkage data indicate that cryptic (asymptomatic) and late-onset (symptomatic) 21-hydroxylase deficiency result from the same allelic variant at the steroid 21-hydroxylase locus. A glossary of terms is presented to describe the various allelic forms of 21-hydroxylase deficiency with consistency.

Genetic and hormonal characterization of cryptic 21-hydroxylase deficiency.

Cryptic 21-hydroxylase deficiency has been previously described in asymptomatic family members of patients with classical congenital adrenal hyperplasia (CAH). These family members were detected by high baseline 17-hydroxyprogesterone levels found in the course of family studies. The hormonal responses to ACTH of the family members with cryptic 21-hydroxylase deficiency were determined and compared to the responses of patients with CAH, patients with acquired adrenal hyperplasia, family members predicted to be heterozygous for CAH, family members predicted to be unaffected, and the general population. The ACTH-stimulated levels of 17-hydroxyprogesterone and delta 4-androstenedione in the cryptic family members were elevated above the level of the general population or family members heterozygous for classical CAH, but below that of patients with CAH. The hormonal profile of patients with cryptic 21-hydroxylase deficiency is similar to that of patients with acquired adrenal hyperplasia. The response of family members heterozygous for the cryptic gene (21-OH CRYPTIC/21-OH NORMAL) was indistinguishable from that of family members heterozygous for the classical CAH gene (21-OH CAH/21-OH NORMAL). These studies support our previous proposal that patients with cryptic 21-hydroxylase deficiency are genetic compounds, having one gene for a severe enzyme deficiency and one gene for a mild 21-hydroxylase deficiency. Thus, the 21-hydroxylase genotype in cryptic 21-hydroxylase deficiency is 21-OH CAH/21-OH CRYPTIC.

HLA linkage and B14, DR1, BfS haplotype association with the genes for late onset and cryptic 21-hydroxylase deficiency.

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH-def) has been established to be an HLA-linked, recessive monogenetic disease. However, two nonclassical forms of 21-OH-def have also been described: "cryptic" 21-OH-def, which has been shown to be HLA-linked, and "late onset" 21-OH-def, for which the status of linkage to HLA has been less certain. We now describe studies of eight additional unrelated probands with symptomatic, "late onset" 21-OH-def, and conclude that this form is also HLA-linked. Both "late onset" and "cryptic" 21-OH-def are highly associated with the same HLA antigens and markers (HLA-B14, HLA-DR1, and Bf type S) in individuals from different ethnic and geographical backgrounds. Since both "late onset" and "cryptic" 21-OH-def appear to occur in individuals with one classical 21-OH-def (21-OHCAH) allele who in addition have another 21-OH-def allele, as well as in individuals who appear to be homozygous for variant 21-PH-def alleles, and since both late onset and cryptic 21-OH-def appear to occur in the same families, our data suggest that these syndromes may represent different clinical expressions of similar or identical nonclassical 21-OH-def alleles.

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.

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

HLA 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.