Two puzzling cases of thyroid dysgenesis.

BACKGROUND: In the last couple of years, different genes that play major roles in embryonic thyroid development have been identified. Several mutations, e.g., NKX2.1, FOXE1 and PAX8, were identified in patients with congenital hypothyroidism due to thyroid dysgenesis. However, the pathophysiology of most cases of thyroid dysgenesis remains unknown. Due to the sporadic occurrence and discordance observed in monozygotic twins, a classic genetic hypothesis for thyroid dysgenesis is improbable. CASE REPORT: We present two pairs of monozygotic twins discordant for thyroid dysgenesis that exemplify these conceptual difficulties. CONCLUSIONS: Identification of the epigenetic differences observed in monozygotic twins discordant for thyroid dysgenesis may be crucial in discovering the pathogenesis of thyroid dysgenesis.

First small supernumerary ring chromosome carrying 10q euchromatin in a patient with mild phenotype characterized by molecular cytogenetic techniques and review of the literature.

We report the identification and characterization of the first supernumerary ring chromosome 10 containing a considerable proportion of 10q euchromatin by microdissection and reverse painting in a female patient presenting with short stature. Fluorescence in situ hybridization studies showed that the marker chromosome originates from chromosome 10 and includes the euchromatic bands p11.2 and q11.2. The supernumerary marker chromosome 10 was found in 14% of the peripheral blood lymphocytes analyzed. This constitutional mosaic could be confirmed in oral mucosa cells as a second cell system (16%) by interphase FISH using an alphoid centromeric probe for chromosome 10. Parental karyotypes were normal, uniparental disomy for the normal chromosomes 10 could be excluded by microsatellite analysis. The karyotype of the patient detected in peripheral blood cells can be described as mos 47,XX,+mar.rev ish r(10)(p11.2q11.2)(wcp10+,cep10+)/46,XX.

Screening chromosomal aberrations by array comparative genomic hybridization in 80 patients with congenital hypothyroidism and thyroid dysgenesis.

OBJECTIVE: Congenital hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis (TD), represents 80% of permanent congenital hypothyroidism cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with nonsyndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its etiology. METHODS: The introduction of array comparative genomic hybridization (CGH) has provided the ability to map DNA copy number variations (CNVs) genome wide with high resolution. We performed an array CGH screen of 80 TD patients to determine the role of CNVs in the etiology of the disease. RESULTS: We identified novel CNVs that have not been described as frequent variations in the healthy population in 8.75% of all patients. These CNVs exclusively affected patients with athyreosis or thyroid hypoplasia and were nonrecurrent, and the regions flanking the CNVs were not enriched for segmental duplications. CONCLUSIONS: The high rate of chromosomal changes in TD argues for an involvement of CNVs in the etiology of this disease. Yet the lack of recurrent aberrations suggests that the genetic causes of TD are heterogenous and not restricted to specific genomic hot spots. Thus, future studies may have to shift the focus from singling out specific genes to the identification of deregulated pathways as the underlying cause of the disease.

Epidermal growth factor in mouse milk during early lactation: lack of dependency on submandibular glands.

Using a specific and sensitive radioimmunoassay, we found epidermal growth factor (EGF) in mouse milk during early lactation in normal and sialoadenectomized mice. Levels of EGF peaked around the 6th day postpartum and decreased thereafter up to day 12. Sephadex G-50 column chromatography of milk from normal and sialoadenectomized mice showed a single immunoreactive component comigrating with purified 6045 dalton EGF from the mouse submandibular gland. The concentrations of EGF were similar in milk collected from the breast and the stomach of the offspring immediately after feeding. The molecular profiles, concentrations, and ontogeny of EGF in milk of control and sialoadenectomized mice were also similar, suggesting that the submandibular gland is not the major source of EGF in mouse breast milk.

Nerve growth factor in mouse milk during early lactation: lack of dependency on submandibular salivary glands.

Using a specific and sensitive nerve growth factor radioimmunoassay we show measurable quantities of beta nerve growth factor in mouse milk during the period of early lactation. Partial purification by cationic exchange resin yielded a preparation which exhibited biological activity in a PC-12 cell bioassay system. Submandibular-sublingual sialoadenectomy had no influence on the breast milk NGF concentrations. These results support the presence of bioactive NGF in mouse milk during early lactation, but do not clarify the source.

Acquisition of submandibular gland nerve growth factor (SMG-NGF) responsiveness to thyroxine administration in neonatal mice.

The growth of the submandibular gland (SMG) was studied in newborn mice from birth to 15 days of age. Progressive changes in wet weight were observed to accompany changes in biochemical constituents such as RNA, protein, and lipid. Thyroxine (T4) administration from days 0-6 produced changes in SMG growth and SMG accumulation of RNA, protein, and lipid components relative to control pups treated with a similar volume of vehicle. This hormone regimen produced no measurable changes in SMG nerve growth factor (SMG-NGF) concentration. T4 responsiveness also was studied from days 0-15. Three patterns of T4 injection (from days 0-6, 7-14, and 0-14) were found to elicit a differential response in the three biochemical constituents measured, but treatment from days 7-14 and 0-14 elicited precocious increments in SMG-NGF concentrations on day 15. The effect of T4 injection from birth was more effective in augmenting SMG-NGF concentration than hormone treatment initiated from days 7-14. A persistent T4 effect on SMG-NGF also was observed on day 21 following hormone treatment from days 7-14 or 0-14. In summary, the acquisition of SMG-NGF responsiveness to T4 appears to develop during the neonatal period. The administration of T4 during this period also precociously stimulates the mechanisms that govern the normal ontogeny of SMG-NGF at the time of weaning.

Molecular analysis of the PDS gene in Pendred syndrome.

Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. Within the thyroid gland of affected individuals, iodide is incompletely organified with variable effects upon thyroid hormone biosynthesis, whilst the molecular basis of the hearing loss is unknown. The PDS gene has been identified by positional cloning of chromosome 7q31, within the Pendred syndrome critical linkage interval and encodes for a putative ion transporter called pendrin. We have investigated a cohort of 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families (includes three homozygous consanguineous kindreds and one extended family segregating three mutant alleles). Moreover, four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis would favour common founders rather than mutational hotspots within the PDS gene. Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.