Ram K. Menon

Relaxation of imprinting in Prader-Willi syndrome

Abstract We describe two Prader-Willi syndrome (PWS) patients who exhibit maternal uniparental disomy (UPD) of chromosome 15 and unusual patterns of gene expression and DNA replication. Both were diagnosed during infancy as having PWS; however, their growth and development were atypical compared with others with this condition. Weight was below normal in the first patient, and height and development were within normal limits in the second individual. Hyperphagia and polyphagia were not evident in either patient. Genotypes at multiple genomic loci, allele-specific methylation, gene expression, and DNA replication were analyzed at D15S9 [ZNF127], D15S63 [PW71], SNRPN, PAR5, IPW, and D15S10 in these patients. The maternal imprint (based on the absence of gene expression, synchronous replication, and methylation of both alleles) was retained at SNRPN in these patients, as is the case in others with UPD. By contrast, cells from the first individual expressed PAR5 and ZNF127, whereas the second expressed a single IPW allele. Asynchronous DNA replication was observed in both patients at all loci, except SNRPN. These findings show that a subset of imprinted genes can be transcribed in some PWS patients with maternal UPD and that asynchronous DNA replication is coordinated with this pattern of gene expression. Relaxed imprinting in these patients is consistent with their milder phenotype.

Residual Thyroid Tissue After Thyroidectomy in a Patient With TSH Receptor-Activating Mutation Presenting as a Neck Mass

BACKGROUND Activating mutations of the TSH receptor (TSHR) are rare, with few reported cases of long-term follow-up. CASE We present a follow-up report on a patient with neonatal thyrotoxicosis known to have a rare activating mutation of the TSHR, a heterozygous substitution in exon 10 (p.Ile568Thr). Initial treatment included total thyroidectomy at age 2 ½ years, resulting in iatrogenic hypothyroidism and hypoparathyroidism. The patient was treated with levothyroxine replacement to maintain TSH levels within normal range, as well as calcitriol and calcium carbonate to treat postsurgical hypoparathyroidism. However, 4 years later, while euthyroid, he developed a palpable 1-cm midline neck mass. METHODS AND RESULTS Functional imaging with 123-I thyroid scan demonstrated active thyroid tissue within the thyroglossal duct remnant and in the tracheoesophageal groove. Surgical removal of the neck mass revealed cytologically bland thyroid follicular cells. CONCLUSION These findings suggest that even after total thyroidectomy, patients with TSHR-activating mutations are at risk to develop significant quantities of functional thyroid tissue related to the hypertrophy of residual foci in the thyroid bed and in the thyroglossal duct remnant. These residual foci may enlarge and secrete thyroid hormones autonomously, decreasing the patients levothyroxine requirement. Surveillance with serial physical examination and biochemical monitoring is recommended; suspicious findings can be further evaluated with functional thyroid imaging (99-m technetium or radioiodine 123-I thyroid scans) to adequately identify residual foci of thyroid tissue, which may require further treatment with surgical excision or radioablation.

Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes

Abstract We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

Limitations of first‐phase insulin response to evaluate insulin secretion in children

The first‐phase insulin response (FPIR) is a widely used method to evaluate beta‐cell function during the prediabetic phase of evolving type 1 diabetes mellitus (DM). The aim of the present study was to evaluate the influence of clinical and methodological variables on FPIR in normal children and adolescents.
 Children and adolescents who were first‐degree relatives of those with type 1 DM and healthy young adults were studied. All subjects were islet cell antibody‐negative. A FPIR test was performed on all subjects while fasting. Insulin samples were drawn at 0, 1, 2, 3, 4, 5, 6, 8, and 10 min after 0.3 g/kg of dextrose. FPIR(1–10) was calculated as the area under the FPIR curve corrected for baseline.
 Eighty‐five subjects aged 4–22 yr were studied, 43 of whom were pre‐pubertal, 24 pubertal, and 18 post‐pubertal. FPIR(1–10) values were lower in the pre‐pubertal group when compared to either the pubertal and post‐pubertal groups (415 [179–965, 2SD], 756 [256–2 223] and 684 [235–1 180] mU/L, respectively; p<0.05). Obese subjects had a higher FPIR than non‐obese subjects (856 vs. 520 mU/L; p<0.005). Despite correcting for the influence of puberty and obesity, there remained considerable unaccounted variability in FPIR(1–10) (R=0.46). Further variables found to influence FPIR(1–10) were: fasting insulin level (r2=0.49); weight for length index (r2=0.38); peak blood glucose level (r2=0.38, all p<0.001); and pre‐pubertal age (r2=0.20, p<0.05).
 Conclusion: FPIR exhibited wide inter‐subject variability and was influenced by a number of clinical and methodological factors that make interpretation more difficult without more specifically defined standards.

Developmental Endocrinology in the Fetal-Placental Unit

The placenta is a tissue of fetal origin embedded in the maternal uterine wall that permits exchange of vital nutrients and other elements essential for fetal growth, development, and survival. In addition, the placenta is a tissue capable of steroid and polypeptide synthesis. Hormonal products and interconversions resulting from these synthetic pathways appear to be critically important for ordered fetal growth and development. In some instances, notably estradiol (E2) and estriol (E3) synthesis, the placenta converts steroid precursors synthesized in the fetal adrenal. Thus, in this instance, the placenta completes a task initiated in the fetal adrenal so that the fetus and placenta act as a unit, the fetoplacental unit. This chapter discusses endocrine aspects of the fetalplacental unit during gestation and their relevance to the physiology of normal intrauterine development as well as selected examples of pathologic disorders.