Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians
Abstract
CONTEXT: Congenital lipoid adrenal hyperplasia (CLAH), caused by mutations in steroidogenic acute regulatory protein (StAR), is most frequent in Japanese and Palestinians. We report eight Palestinians from four unrelated families with CLAH. OBJECTIVE: The objective of the study was to identify the mutation(s) in StAR, correlate genotype with phenotype, and determine whether the common mutation represents a founder mutation. PATIENTS AND SETTING: Clinical, histopathological, and molecular genetic characterization was performed in these eight patients. RESULTS: All affected individuals (three XY, five XX) presented neonatally with undetectable adrenocortical hormones and are responding to replacement therapy. Only two sisters had neurodevelopmental deficits. Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells. Significantly, already at 1 yr of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of StAR revealed homozygosity for c.201_202delCT mutation in all eight cases, causing premature termination of the StAR protein. This mutation was confirmed to be a founder mutation using both an intragenic microsatellite and several single nucleotide polymorphism markers. Screening of 100 normal Jerusalem Palestinians detected no carriers of this mutation. CONCLUSION: CLAH is rare in the general Palestinian population. In most Palestinian cases, a founder c.201_202delCT mutation in StAR is the cause. The observed early neonatal presentation may reflect the major StAR protein truncation caused by this mutation. A crucial role for StAR in the central nervous system was not supported with normal neurological examinations in six of eight cases. Finally, we advocate early gonadectomy in XY CLAH cases, given the early onset of neoplastic changes observed histologically.
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Most CAH patients with 21OH deficiency prefer early surgery.
“Most CAH patients with 21OH deficiency prefer early surgery.76”
From Congenital adrenal hyperplasia (2017) · cites this paper as [76]
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- Authors
- Abdulhadi-Atwan, M., Jean, A., Chung, W. K., Meir, K., Ben Neriah, Z., Stratigopoulos, G., Oberfield, S. E., Fennoy, I., Hirsch, H. J., Bhangoo, A., Ten, S., Lerer, I., & Zangen, D. H.
- Affiliations
- Division of Pediatric Endocrinology (M.A.-A., D.H.Z.), Hadassah Hebrew University Medical Center, Jerusalem, Israel 91240
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Hadassah Medical Center (IL)
- Departments of Human Genetics (Z.B.N., I.L.), Hadassah Hebrew University Medical Center, Jerusalem, Israel 91240
- Shaare Zedek Medical Center (IL)
- Maimonides Medical Center (US)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Zangen, David H.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2007-10-01
- Volume
- 92
- Issue
- 10
- Pages
- 4000-4008
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2066038944
- Cited by
- 37
- References
- 37
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2014: 3 · 2013: 4 · 2012: 4
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital lipoid adrenal hyperplasia, steroidogenic acute regulatory protein, stars, founder mutation, genotype-phenotype correlation, premature stop codon, placental alkaline phosphatase, gonadectomy, neurodevelopmental deficits, adrenal insufficiency, Palestinian population
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adrenal Hyperplasia, Congenital, Child, Child, Preschool, Chromosomes, Human, Pair 8, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Pedigree, Phenotype, Phosphoproteins, Testis, Founder Effect, Arabs
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