Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature.
BACKGROUND
3β-hydroxysteroid dehydrogenase deficiency (3βHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3βHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk.


OBJECTIVE
To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation.


METHODS
Biochemical, genetic and immunohistochemical investigations on human biomaterials.


RESULTS
A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes.


CONCLUSIONS
The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Marie-Anne
MA
Burckhardt
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Sameer S
SS
Udhane
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Nesa
N
Marti
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Isabelle
I
Schnyder
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Coya
C
Tapia
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
John E
JE
Nielsen
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Primus E
PE
Mullis
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Ewa
E
Rajpert-De Meyts
Pediatric Endocrinology and DiabetologyDepartments of Pediatrics and Clinical ResearchPediatric SurgeryInstitute of PathologyUniversity of Bern, CH-3010 Bern, SwitzerlandDepartment of Growth and ReproductionRigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark christa.flueck@dkf.unibe.ch.
Christa E
CE
Flück
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007231:Infant, Newborn; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D009154:Mutation; D011627:Puberty / Q000235:genetics*; D013737:Testis / Q000473:pathology*