Alon Haim

The utility of basal serum LH in prediction of central precocious puberty in girls

OBJECTIVE The mainstay of distinction between prepubertal girls and girls who are suspected of having central precocious puberty (CPP) is based on gonadotropin measurements after a GnRH stimulation test to evaluate hypothalamic-pituitary-gonadal axis maturity. The objective of this study was to determine whether a single basal gonadotropin measurement carries a useful predictive value in verifying or refuting the diagnosis of CPP. DESIGN AND METHODS Basal serum LH and FSH were measured by a chemiluminescent immunometric assay in a cohort of girls who had been evaluated for CPP before and after GnRH stimulation test. Peak LH levels higher than 5 IU/l were considered a pubertal response. RESULTS Eighty girls with suspected breast development before 8 years of age were enrolled to the study, out of whom 42 had CPP. Low basal serum LH (≤0.1 IU/l) was sufficient to rule out the diagnosis of CPP in 94.7% of the 38 prepubertal girls; the sensitivity of basal LH levels for this purpose was only 64%. The basal FSH and the basal LH to FSH ratio achieved less efficient predictive value with 76 and 71% sensitivity and 73 and 86% specificity respectively. CONCLUSION A single basal LH measurement may be adequate to confirm but not to refute the presence of CPP in most of the girls who are evaluated for early pubertal signs.

Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency

Phosphoglucomutase 1 (PGM1, EC 5.4.2.2) plays a critical role in glucose homeostasis and is also essential for protein N‐glycosylation. The main clinical manifestations of PGM1 deficiency (MIM 614921) reported in 19 patients from different ethnic backgrounds include the following: cleft uvula/palate, Pierre Robin sequence, muscle weakness, dilated cardiomyopathy, growth retardation, elevated serum transaminases, hypoglycemia, and various endocrine abnormalities. We report the variable clinical picture of seven patients with PGM1 deficiency from a consanguineous family. Medical records of the patients were reviewed for clinical details and endocrine evaluation. Whole exome sequencing (WES) was performed. Seven patients aged 2–29 years were included, one patient died at 13 years old when getting off the school bus. All patients have an abnormal palatine structure (cleft palate, bifid uvula) and elevated serum transaminases, 4/7 have short stature (<−2 SDS) and one was diagnosed with growth hormone deficiency. Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients. In two patients, hypoglycemic episodes have spontaneously resolved later on. Four out of seven patients have deteriorating adrenal function with abnormally low cortisol and ACTH levels during hypoglycemia and subnormal response of cortisol to low dose ACTH test . Serum electrolytes were within normal range. Hydrocortisone replacement therapy improved, but not entirely eliminated hypoglycemic episodes. WES revealed a previously described homozygous mutation c.112A>T, p.Asn38Tyr in the PGM1 gene. The clinical picture of PGM1 deficiency is variable among patients with the same mutation and genetic background. ACTH deficiency should be considered in any PGM1 deficient patient with hypoglycemia.

Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus†

Alpha‐1 antitrypsin (AAT) has been shown to reduce pro‐inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM).

Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency

Abstract Objective: The nicotinamide nucleotide transhydrogenase (NNT) enzyme is the main generator of nicotinamide adenine dinucleotide phosphate-oxidase in the mitochondrion. Mutations of the NNT gene have been recently implicated in familial glucocorticoid deficiency. We describe the long-term clinical course of a NNT-deficient 20-year-old patient with combined adrenal failure who had developed a testicular adrenal rest tumor and precocious puberty. Methods: The patient’s medical records were reviewed. Whole-exome sequencing was performed on DNA obtained from the patient and family members. Results: The patient experienced Addisonian crisis at 10 months of age. Enlarged testicular volume and precocious puberty, accompanied by increased testosterone levels, were noted at 6 years. Testicular biopsy revealed a adrenal rest tumor, which regressed after intensification of glucocorticoid treatment. Genetic studies disclosed a c.1163A>C, p.Tyr388Ser substitution on the NNT gene. This mutation is predicted to be damaging to NNT function. Conclusion: We demonstrated for the first time that the clinical spectrum of NNT deficiency may consist of mineralocorticoid deficiency and testicular involvement as well.