Calcitonin secretion in congenital nongoitrous cretinism.

Plasma calcitonin (CT) was measured in the basal state and/or during provocative tests of hormone secretion in 11 children with congenital non-goitrous cretinism (CNC), in 1 girl with a lingual thyroid, and in 11 normal children. Basal and stimulated CT concentrations were significantly lower in the patients with CNC than in the normal subjects. Mean basal CT (+/- SE) was 41 +/- 4 pg/ml in the normal children, 24 +/- 3 pg/ml in the children with CNC, and 20 +/- 2 pg/ml in the patient with the lingual thyroid. The mean incremental CT responses to calcium infusion were 7.0 +/- 2 pg/ml in the children with CNC, 6.0 pg/ml in the patient with the lingual thyroid, and 146 +/- 47 pg/ml in the normal children. The children with CNC also demonstrated a significant delay in the return of the total serum calcium to basal level after the calcium infusion. The mean incremental CT response after infusion of pentagastrin was 7.6 +/- 2 pg/ml in the children with CNC, 10.0 pg/ml in the child with the lingual thyroid, and 34.4 +/- 11 pg/ml in the normal children. These data indicate that CT deficiency is present in children with CNC and suggest that the deficiency is a consequence of the defective embryologic development of the thyroid gland.

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

The most severe brain damage associated with thyroid dysfunction during development is observed in neurological cretins from areas with marked iodine deficiency. The damage is irreversible by birth and related to maternal hypothyroxinemia before mid gestation. However, direct evidence of this etiopathogenic mechanism is lacking. Rats were fed diets with a very low iodine content (LID), or LID supplemented with KI. Other rats were fed the breeding diet with a normal iodine content plus a goitrogen, methimazole (MMI). The concentrations of -thyroxine (T4) and 3,5,3'triiodo--thyronine (T3) were determined in the brain of 21-d-old fetuses. The proportion of radial glial cell fibers expressing nestin and glial fibrillary acidic protein was determined in the CA1 region of the hippocampus. T4 and T3 were decreased in the brain of the LID and MMI fetuses, as compared to their respective controls. The number of immature glial cell fibers, expressing nestin, was not affected, but the proportion of mature glial cell fibers, expressing glial fibrillary acidic protein, was significantly decreased by both LID and MMI treatment of the dams. These results show impaired maturation of cells involved in neuronal migration in the hippocampus, a region known to be affected in cretinism, at a stage of development equivalent to mid gestation in humans. The impairment is related to fetal cerebral thyroid hormone deficiency during a period of development when maternal thyroxinemia is believed to play an important role.

Intellectual outcome at 12 years of age in congenital hypothyroidism.

BACKGROUND: The intellectual outcome in children with congenital hypothyroidism detected by neonatal screening is generally good; however, subtle neurological dysfunctions, subnormal IQ, or both, have been reported. OBJECTIVE: To evaluate the intellectual outcome in 12-year-old patients with congenital hypothyroidism, detected by neonatal screening, in an attempt to identify factors that may affect intellectual development. METHODS: The intelligence quotient (IQ) of 40 children with congenital hypothyroidism was evaluated at 12 years of age, using the Wechsler Intelligence Scale for Children -- Revised, and compared with the IQ of 40 healthy siblings (control group). RESULTS: The mean IQ score (88.4+/-13.1) was not significantly different from that of the control group (93.4+/-10.7). Thirteen patients showed subnormal IQ score (72.4+/-4.9) compared with their siblings (86.7+/-9.6; P<0.0001) and with the other patients (96.1+/-9.6; P<0.0001). The low IQ score was associated with lower serum concentrations of thyroxine at diagnosis, poor treatment compliance during follow-up and lower familial IQ. Interviews with parents of children with congenital hypothyroidism revealed that a refusal to acknowledge the disease was linked to poor attention to the child's emotional life and to poor treatment compliance in some cases (11%). CONCLUSION: Even though the mean IQ score in patients with congenital hypothyroidism falls within normal for the control population, low IQ scores may be present in patients with severe hypothyroidism, inadequate compliance to replacement therapy during follow-up and poor parental pedagogic attitude.

A controlled trial of iodinated oil for the prevention of endemic cretinism: a long-term follow-up.

A double blind controlled trial designed to examine the effectiveness of intramuscular iodinated oil as a prophylactic for the nervous type of endemic cretinism was begun in 1966 in the highlands of Papua New Guinea. Infants born into the trial between 1966 and 1972 were followed up until 1982. The results showed that if the iodine supplement was given before conception the nervous form of endemic cretinism was prevented. Also a striking difference in the 15-year cumulative survival rate in favour of the test (iodinated oil) group was observed. Measures of motor and intellectual function revealed that children born to mothers given an iodine supplement performed significantly better. This observation shows that iodine deficiency leads to sub-clinical as well as clinical deficits. It also justifies the use of the term iodine deficiency disorder to cover the polymorphic nature of the abnormalities attributable to iodine deficiency.

Expression of mRNAs coding for the transforming growth factor-beta receptors in brain regions of euthyroid and hypothyroid neonatal rats and in adult brain.

The TGF-beta family of peptides has been postulated to play a role in control of the cell cycle but also may act in the developing brain to influence neuronal differentiation and survival. Because reception of TGF-beta signals requires the simultaneous expression of all three known receptor subtypes, we examined two neonatal rat brain regions in which neurogenesis has been largely completed. mRNA coding for all three receptors was detectable in both the forebrain and brainstem but only the type II receptor in brainstem showed a difference from adult levels of expression. Animals given perinatal PTU treatment to achieve congenital cretinism did not show significant differences in expression of any of the receptor subtypes in either of the regions, despite the fact that the treatment is known to cause anomalies of neuronal differentiation. These results indicate that regions in which neurons are undergoing axonogenesis and synaptogenesis rather than neurogenesis, nevertheless express the mRNAs coding for TGF-beta receptors and are thus likely to be receptive to trophic signals mediated through TGF-beta. However, synthesis and release of TGF-beta, rather than receptor expression per se, is more likely to be the major point for regulation of signaling. The potential roles of TGF-beta in developmental events outside of the cell cycle, such as synaptogenesis and apoptosis, need to be examined.

Metabolic maladaptation: individual and social consequences of medical intervention in correcting endemic hypothyroidism.

Endemic hypothyroidism has been studied in a Central African population in remote Congo (ex-Zaire) to investigate the prevalence, severity, causes, and potential control of this disorder, with questions as to why this disease is conserved, and whether it confers any adaptive advantage in this resource-constrained environment. Iodine deficiency, cassava goiterogens, and selenium deficiency were found to be the factors implicated in the severe hypothyroidism expressed in congenital cretinism and high goiter incidence in this isolated population, which continues to be under observation following medical intervention. Profound hypothyroidism was encountered in whole village populations as measured by serum thyrotropin determinations ranging from very high to over 1000 IU, and thyroxin levels ranging from low to undetectable; cretinism rates were as high as 11% and goiter incidence approached 100%. Assessment of endocrinologic status, caloric requirement, energy output, fertility, and ecologic factors was carried out before and during iodine repletion by depot injection. Hypothyroidism was corrected and cretinism eliminated in the treatment group, with goiters reduced in most instances (with regrowth exhibited in some who escaped control) and some symptomatic goiter patients were offered surgical treatment for respiratory obstruction. Individual patient benefits, including improved strength and increased energy output, were remarkable. The social and developmental consequences observed within the collective groups of treated patients were remarkable for an increase in caloric requirement and a dramatic increase in fertility that led to quantitative as well as qualitative increases in resource consumption. Micronutrient iodine repletion was not accompanied by any concomitant increase in macronutrient supply, and hunger and environmental degradation resulted. The highly prevalent disease of hypothyroidism is found in highest incidence in areas of greatest resource constraint. It may be that hypothyroidism is conserved in such areas because it may confer adaptive advantage in such marginal environments as an effect, as well as a cause, of underdevelopment. Hypothyroidism may limit energy requirements, fertility, and consumer population pressure in closed ecosystems that could otherwise be outstripped. Single factor intervention in a vertical health care program not sensitive to the fragile biologic balance and not part of a culture-sensitive development program might result in medical maladaptation.

[Missed diagnosis: a case of congenital hypothyroidism treated after three years]. / Una diagnosi mancata: un caso di ipotiroidismo congenito trattato a 3 anni.

Congenital hypothyroidism (CH) is the most common cause of preventable mental retardation. Thyroid hormone deficiency in utero and in the first neonatal months is responsible for permanent damage. While foetal hypothyroidism is at present unavoidable, earlier diagnosis and initiation of treatment in neonates with CH is important and highly recommended. At the moment, the Italian screening program for CH allows diagnosis and treatment within the first month of life. In Italy, screening programs became obligatory only a short time ago. In some regions, they started a few years ago, whereas in others they have been carried out only in an irregular way and only a part of the population has been investigated. Therefore CH was diagnosed just on the basis of clinical signs, with a consequent delay in the initiation of substitutive therapy. We describe the case of a little girl with CH diagnosed when she was three years old. We report the results of this case follow-up study and we describe the features of her neuropsychological development to point out her improvement and permanent disorders. The little girl was clearly hypothyroid with delayed achievement at three, but with pharmacological treatment she showed a dramatic amelioration in growth, language, motor skills and cognitive performances.

Massive pericardial effusion in an adult case of congenital hypothyroidism due to a sublingual thyroid.

Acquired hypothyroidism is known to cause cardiac tamponade. However, pericardial effusion in cretinism in adulthood has rarely been reported. A 27-year-old dwarfish woman suffering from congestive heart failure was diagnosed with congenital hypothyroidism due to the presence of a sublingual thyroid. The patient had never received thyroid therapy until the time of diagnosis at age 27. Despite the existence of massive pericardial effusion, the patient had hypertension. Her metabolic abnormality responded dramatically to L-thyroxin. Pericardial effusion disappeared one year after the initiation of medical treatment.

Alterations of neonatal thyroid function.

Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations.

[Molecular pathology of congenital pituitary hypothyroidism--discovery of new clinical entities].

Congenital pituitary hypothyroidism (pituitary cretinism) results in severe mental and growth retardation when it is not treated soon after birth. Since the introduction of neonatal mass screening of thyrotropin (TSH), most congenital hypothyroidism has been detected except for pituitary and hypothalamic hypothyroidism. In 1971, we reported the first familial case of congenital isolated TSH deficiency and thereafter began intensively investigating the molecular pathology of congenital pituitary hypothyroidism. After determining the entire structure of the human TSH beta gene, we identified the molecular pathology in this patient. Recently, we reported a familial case of congenital combined pituitary hormone deficiency (PIT1 abnormality). To examine the PIT1 gene, which encodes pituitary specific transcription factor, Pit-1/GHF-1, we determined its genomic structure. Sequence comparisons using PCR amplified PIT1 gene sequences revealed only one nonsense mutation in the patient, and established that this alteration caused the combined deficiencies of TSH, GH and PRL. We also discuss other recent progress in molecular pathology of congenital pituitary hypothyroidism.

Low incidence of X-chromatin in congenital hypothyroidism.

Buccal smears of 5 female patients with hypothyroidism (3 with congenital hypothyroidism or cretinism and 2 with acquired type) were studied for X-chromatin. Very low incidence of X-chromatin positive cells (1.33%, 1.59% and 2.06%) was found in all the three cases with cretinism while the incidence was the same (15.0% and 15.61%) as in the control females (15.5%), in 2 cases with acquired hypothyroidism. Chromosome studies were carried out in two cases of cretinism. They had a normal karyotype, 46 XX.