Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency
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Ahmed Khattab
Abstract
Steroid 17β-hydroxysteroid dehydrogenase III (17β-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17β-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Δ4) to testosterone (T). Such 17β-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5α-reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17β-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17β-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis.
References
1. Lukacik P, Kavanagh KL, Oppermann U. Structure and function of human 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 2006;248:61–71.10.1016/j.mce.2005.12.007Search in Google Scholar
2. Mendonca BB, Costa EM, Inacio M, Oliveira Junior AA, Martin RM, et al. Chapter 3K – 46,XY DSD due to 17β-Hydroxysteroid Dehydrogenase 3 Deficiency. In: New MI, Lekarev O, Parsa A, Yuen TT, O’Malley BW, Hammer GD, editors. Genetic Steroid disorders. San Diego: Academic Press, 2014:191–7.Search in Google Scholar
3. Inacio M, Sircili MH, Brito VN, Domenice S, Oliveira-Junior AA, et al. 46,XY DSD due to 17beta-HSD3 deficiency and 5alpha-reductase type 2 deficiency. Adv Exp Med Biol 2011;707:9–14.10.1007/978-1-4419-8002-1_3Search in Google Scholar
4. Mendonca BB, Inacio M, Arnhold IJ, Costa EM, Bloise W, et al. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management. Medicine (Baltimore) 2000;79: 299–309.10.1097/00005792-200009000-00003Search in Google Scholar
5. George MM, New MI, Ten S, Sultan C, Bhangoo A. The clinical and molecular heterogeneity of 17betaHSD-3 enzyme deficiency. Horm Res Paediatr 2010;74:229–40.10.1159/000318004Search in Google Scholar
6. Cohen-Kettenis PT. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 2005;34: 399–10.10.1007/s10508-005-4339-4Search in Google Scholar
7. Wilson JD. Androgens, androgen receptors, and male gender role behavior. Horm Behav 2001;40:358–66.10.1006/hbeh.2001.1684Search in Google Scholar
8. Rosler A, Kohn G. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: studies on the natural history of the defect and effect of androgens on gender role. J Steroid Biochem 1983;19:663–74.10.1016/0022-4731(83)90233-9Search in Google Scholar
9. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 1979;300:1233–7.10.1056/NEJM197905313002201Search in Google Scholar PubMed
10. Imperato-McGinley J, Peterson RE, Stoller R, Goodwin WE. Male pseudohermaphroditism secondary to 17 beta-hydroxysteroid dehydrogenase deficiency: gender role change with puberty. J Clin Endocrinol Metab 1979;49:391–5.10.1210/jcem-49-3-391Search in Google Scholar PubMed
11. Alikasifoglu A, Hiort O, Gonc N, Demirbilek H, Isik E, et al. 17beta-hydroxysteroid dehydrogenase type 3 deficiency as a result of a homozygous 7 base pair deletion in 17betaHSD3 gene. J Pediatr Endocrinol Metab 2012;25:561–3.10.1515/jpem-2012-0009Search in Google Scholar PubMed
12. Wierenga KJ, Jiang Z, Yang AC, Mulvihill JJ, Tsinoremas NF. A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents. Genet Med 2013;15:354–60.10.1038/gim.2012.136Search in Google Scholar PubMed PubMed Central
13. Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, et al. Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab 1996;81:130–6.Search in Google Scholar
14. Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, et al. A map of human genome variation from population-scale sequencing. Nature 2010;467:1061–73.10.1038/nature09534Search in Google Scholar PubMed PubMed Central
15. Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, et al. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Nat Genet 1994;7:34–9.10.1038/ng0594-34Search in Google Scholar PubMed
16. Castro CC, Guaragna-Filho G, Calais FL, Coeli FB, Leal IR, et al. Clinical and molecular spectrum of patients with 17beta-hydroxysteroid dehydrogenase type 3 (17-beta-HSD3) deficiency. Arq Bras Endocrinol Metabol 2012;56:533–9.10.1590/S0004-27302012000800012Search in Google Scholar
17. Boehmer AL, Brinkmann AO, Sandkuijl LA, Halley DJ, Niermeijer MF, et al. 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 1999;84:4713–21.Search in Google Scholar
©2015 by De Gruyter
Articles in the same Issue
- Frontmatter
- Highlight: Obesity
- Childhood obesity at the crossroads
- Obesogenic environments: environmental approaches to obesity prevention
- Childhood obesity and eating behaviour
- Hypothalamic obesity in children: pathophysiology to clinical management
- The reliability of body mass index in the diagnosis of obesity and metabolic risk in children
- Determining abdominal obesity cut-offs and relevant risk factors for anthropometric indices in Turkish children and adolescents
- The effect of body mass index on blood pressure varies by race among obese children
- Insulin secretion response during oral glucose tolerance test is related to low cardiorespiratory fitness in obese adolescents
- Is there a relationship between cardiovascular risk factors and dehydroepiandrosterone sulfate levels in childhood obesity?
- The effect of lifestyle change and metformin therapy on serum arylesterase and paraoxonase activity in obese children
- Childhood obesity, thyroid function, and insulin resistance – is there a link? A longitudinal study
- Associations between IGF-I, IGF-binding proteins and bone turnover markers in prepubertal obese children
- Osteocalcin is inversely associated with adiposity and leptin in adolescent boys
- Association between cardiovascular risk factors and carotid intima-media thickness in prepubertal Brazilian children
- Insulin resistance and cardiometabolic risk factors in obese children and adolescents: a hierarchical approach
- The role of apolipoprotein E polymorphism in improving dyslipidemia in obese adolescents following physical exercise and National Cholesterol Education Program Step II intervention
- Review article
- Is ultrasound useful in the diagnosis of adolescents with polycystic ovary syndrome?
- Original articles
- IGF-II expression and methylation in small for gestational age infants
- Early screening of FTO and MC4R variants in newborns of Greek origin
- Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency
- The prevalence of vitamin D deficiency among schoolchildren: a cohort study from Xinxiang, China
- Management of testosterone therapy in adolescents and young men with hypogonadism: are we following adult clinical practice guidelines?
- Vitamin D status and its associations with components of metabolic syndrome in healthy children
- Metformin treatment improves weight and dyslipidemia in children with metabolic syndrome
- Patient reports
- Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene
- Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy
- An asymptomatic mother diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency after newborn screening
- A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD)
- Ovotesticular disorder of sex development with unusual karyotype: patient report
- First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China
- Virilizing adrenal oncocytoma in a 9-year-old girl: rare neoplasm with an intriguing postoperative course
- Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency
- Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation
- Cross-reactivity of adrenal steroids with aldosterone may prevent the accurate diagnosis of congenital adrenal hyperplasia
- Hyperthyroidism hidden by congenital central hypoventilation syndrome
- The use of pamidronate for acute vitamin D intoxication, clinical experience with three cases
- Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis
- Cushing syndrome related to leukemic infiltration of the central nervous system
- Hashimoto’s encephalopathy: a rare pediatric brain disease
- Short communication
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Articles in the same Issue
- Frontmatter
- Highlight: Obesity
- Childhood obesity at the crossroads
- Obesogenic environments: environmental approaches to obesity prevention
- Childhood obesity and eating behaviour
- Hypothalamic obesity in children: pathophysiology to clinical management
- The reliability of body mass index in the diagnosis of obesity and metabolic risk in children
- Determining abdominal obesity cut-offs and relevant risk factors for anthropometric indices in Turkish children and adolescents
- The effect of body mass index on blood pressure varies by race among obese children
- Insulin secretion response during oral glucose tolerance test is related to low cardiorespiratory fitness in obese adolescents
- Is there a relationship between cardiovascular risk factors and dehydroepiandrosterone sulfate levels in childhood obesity?
- The effect of lifestyle change and metformin therapy on serum arylesterase and paraoxonase activity in obese children
- Childhood obesity, thyroid function, and insulin resistance – is there a link? A longitudinal study
- Associations between IGF-I, IGF-binding proteins and bone turnover markers in prepubertal obese children
- Osteocalcin is inversely associated with adiposity and leptin in adolescent boys
- Association between cardiovascular risk factors and carotid intima-media thickness in prepubertal Brazilian children
- Insulin resistance and cardiometabolic risk factors in obese children and adolescents: a hierarchical approach
- The role of apolipoprotein E polymorphism in improving dyslipidemia in obese adolescents following physical exercise and National Cholesterol Education Program Step II intervention
- Review article
- Is ultrasound useful in the diagnosis of adolescents with polycystic ovary syndrome?
- Original articles
- IGF-II expression and methylation in small for gestational age infants
- Early screening of FTO and MC4R variants in newborns of Greek origin
- Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency
- The prevalence of vitamin D deficiency among schoolchildren: a cohort study from Xinxiang, China
- Management of testosterone therapy in adolescents and young men with hypogonadism: are we following adult clinical practice guidelines?
- Vitamin D status and its associations with components of metabolic syndrome in healthy children
- Metformin treatment improves weight and dyslipidemia in children with metabolic syndrome
- Patient reports
- Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene
- Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy
- An asymptomatic mother diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency after newborn screening
- A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD)
- Ovotesticular disorder of sex development with unusual karyotype: patient report
- First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China
- Virilizing adrenal oncocytoma in a 9-year-old girl: rare neoplasm with an intriguing postoperative course
- Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency
- Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation
- Cross-reactivity of adrenal steroids with aldosterone may prevent the accurate diagnosis of congenital adrenal hyperplasia
- Hyperthyroidism hidden by congenital central hypoventilation syndrome
- The use of pamidronate for acute vitamin D intoxication, clinical experience with three cases
- Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis
- Cushing syndrome related to leukemic infiltration of the central nervous system
- Hashimoto’s encephalopathy: a rare pediatric brain disease
- Short communication
- A novel ABCD1 gene mutation in a Chinese patient with X-linked adrenoleukodystrophy
