Context:Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective:Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS.Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results:Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.Conclusions:The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

OBJECTIVETransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.RESEARCH DESIGN AND METHODSThe 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.RESULTSThe key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.CONCLUSIONSThere is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.

Following the death of a patient with propionic acidaemia with a cardiomyopathy we reviewed 19 patients with the same disorder for evidence of cardiomyopathy. Six patients were found to meet the diagnostic criteria. Three patients died and in the other three the cardiac disease resolved completely. All patients were treated with standard therapy and some received L-carnitine but this did not seem to influence the eventual outcome. Cardiomyopathy is an important complication of propionic acidaemia and may be rapidly fatal.

Objectives-Transsphenoidal surgery (TSS) is the preferred method for the excision of pituitary microadenomas in adults. This study was carried out to establish the long term eYcacy and safety of TSS in children. Study design-A 14 year retrospective analysis was carried out on 23 children (16 boys and seven girls), all less than 18 years of age, who had undergone TSS at our centre. Results-Twenty nine transsphenoidal surgical procedures were carried out. The most common diagnosis was an adrenocorticotrophic hormone (ACTH) secreting adenoma (14 (61%) patients). The median length of follow up was 8.0 years (range 0.3-14.0 years). Eighteen (78%) patients were cured after the first procedure. No death was related to the operation. The most common postoperative complication was diabetes insipidus, which was transient in most patients. Other complications were headaches in two patients and cerebrospinal fluid leaks in two patients. De novo endocrine deficiencies after TSS in children were as follows: three (14%) patients developed panhypopituitarism, eight (73%) developed growth hormone insuYciency, three (14%) developed secondary hypothyroidism, and four (21%) developed gonadotrophin deficiency. Permanent ACTH deficiency occurred in five (24%) patients, though all patients received postoperative glucocorticoid treatment until dynamic pituitary tests were performed three months after TSS. Conclusions-TSS in children is a safe and eVective treatment for pituitary tumours, provided it is performed by surgeons with considerable experience and expertise. Surgical complications are minimal. Postoperative endocrine deficit is considerable, but is only permanent in a small proportion of patients. (Arch Dis Child 1997;76:398-404)

Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a hexarelin dose of 0.5 microgram/kg. The coadministration of GHRH-(1-29)-NH2 (1.0 microgram/kg) and low dose hexarelin (0.125 microgram/kg) resulted in massive GH release (115 +/- 32.8 mU/L), a moderate rise in serum PRL (84.9 +/- 27.5%), and no rise in serum cortisol. These data show that iv hexarelin was capable of inducing GH, PRL, and cortisol release in a dose-dependent manner. Low dose hexarelin was synergistic with GHRH and potent for GH release with a minimal effect on other hormones.