Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations |
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Authors: | Zohar Landau Aaron Hanukoglu Joseph Sack Nurit Goldstein Naomi Weintrob Alon Eliakim David Gillis Michal Sagi Ruth Shomrat Elka Bella Kosinovsky Yair Anikster |
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Institution: | 1. Division of Pediatric Endocrinology, E. Wolfson Medical Center, Holon and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;2. National Screening for Congenital Hypothyroidism, Ministry of Health, Israel;3. Metabolic Disease Unit, Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;4. Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tiqva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;5. Pediatric Department, Meir Medical Center, Kfar‐Saba, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;6. Pediatric Endocrinology Unit, Hadassah ‐Hebrew University Medical Center, Jerusalem, Israel;7. Department of Human Genetics, Hadassah ‐Hebrew University Medical Center, Jerusalem, Israel;8. Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;9. Department of Pediatric Emergency, Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel |
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Abstract: | Introduction X‐linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX‐1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure. Patients and methods We evaluated the clinical, endocrine and molecular characteristics of 12 AHC patients from 5 families diagnosed between 1984 and 2007 in Israel. Results Most of the boys (10/12) presented with signs of adrenal insufficiency such as salt wasting and failure to thrive during the neonatal period. Aldosterone deficiency usually preceded cortisol deficiency requiring early mineralocorticoid therapy. Serum cortisol levels in the first weeks of life varied from very low to high levels (<2·76 to >1776 nmol/l). Five boys showed signs of precocious sexual development during infancy and childhood, including enlargement of the penis and testes. In four patients the initial diagnoses were erroneous. Molecular analysis of the NR0B1 gene identified point mutations in six patients including a novel splice site mutation in one patient and his family (IVS1‐1G→C). Contiguous gene deletion was found in six patients from two families who manifested impaired mental development. Conclusions In X‐linked AHC caused by different molecular defects in NR0B1 gene, the clinical spectrum of the disease is quite variable and precocious sexual development is a prominent feature. Genetic testing is indicated in boys presenting with salt‐wasting with or without cortisol deficiency if congenital adrenal hyperplasia has been ruled out. |
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