|Year : 2015 | Volume
| Issue : 3 | Page : 90-92
3 Beta-hydroxysteroid Dehydrogenase Deficiency Presenting as Adrenal Crisis in an Infant
Bindu T Nair, Sajith Surendran, Dinesh Yadav
Department of Pediatrics, Army College of Medical Sciences, New Delhi, India
|Date of Web Publication||24-Jul-2015|
Dr. Bindu T Nair
Department of Pediatrics, Army College of Medical Sciences, Delhi Cantt, New Delhi
Source of Support: None, Conflict of Interest: None
Ambiguous genitalia is a birth defect where the external genitals do not have the typical appearance of either a boy or girl. An 8-week-old infant presented with persistent vomiting, failure to thrive, and genital ambiguity. On the basis of clinical presentation, a salt-losing variety of congenital adrenal hyperplasia (CAH) was suspected. Hormonal levels were tested and 3 beta-hydroxysteroid dehydrogenase II (HSD3B2) deficiency, a rare CAH variant was suspected. This was confirmed by molecular analysis of the HSD3B2 gene from the affected baby. It revealed the presence of the homozygous P222Q mutation which was found to be heterozygous in both parents.
Keywords: 3 beta-hydroxysteroid dehydrogenase II deficiency, ambiguous genitalia, salt-wasting crisis
|How to cite this article:|
Nair BT, Surendran S, Yadav D. 3 Beta-hydroxysteroid Dehydrogenase Deficiency Presenting as Adrenal Crisis in an Infant. J Integr Nephrol Androl 2015;2:90-2
|How to cite this URL:|
Nair BT, Surendran S, Yadav D. 3 Beta-hydroxysteroid Dehydrogenase Deficiency Presenting as Adrenal Crisis in an Infant. J Integr Nephrol Androl [serial online] 2015 [cited 2019 Sep 19];2:90-2. Available from: http://www.journal-ina.com/text.asp?2015/2/3/90/161437
| Introduction|| |
Disorders of sex development (DSD) include a varied group of inherited disorders of sex determination and differentiation. This includes chromosomal as well as monogenic disorders. However, in many affected patients, no definitive cause for the disorder can be found. Therefore, the birth of a child with ambiguous genitalia still represents an enormous social as well as medical challenge. Ambiguous genitalia is a medical term for a rare condition in which new-born's external genitals do not appear to be either male or female.  We report an infant with 3 beta-hydroxysteroid dehydrogenase deficiency type II (HSD3B2), a very rare variant of congenital adrenal hyperplasia (CAH).
| Case Report|| |
An 8-week-old baby product of a nonconsanguineous marriage, born by a full term vaginal delivery to a 23-year-old primigravida mother was brought to Pediatric Emergency Department of our hospital with complaints of persistent vomiting for past 1 month, inadequate weight gain, and indistinguishable genitalia. Vomiting was multiple episodes, nonbilious with increased frequency for past 1 month.
It was informed by the parents that as the genitalia was not distinguishable, the gender of the baby was not disclosed by the doctors in the hospital where he was born, and more investigations were required to confirm the sex. There was no history of seizures, chronic diarrhea, or constipation. There was a history of reduced urine output since early neonatal period. There was no history of any infertility treatment or drug intake of androgens or steroids in the mother antenatally. There was no history of any short stature or male infant death reported in the family.
On admission, the baby was alert but fussy and irritable. Weight- 2.7 kg (birth weight- 3 kg), the baby was dehydrated, the pulse rate was 164/min, low volume and poorly palpable. Capillary refill time was prolonged, and peripheries of the baby were cold, blood pressure- 56/32 mm Hg (mean arterial pressure −40 mm Hg). There was pallor and wasting seen in the baby. No hyperpigmentation of digits, dysmorphism, or any other gross congenital defects were seen.
The abdominal examination did not show any flank mass. Genitalia showed ambiguity as evidenced by microphallus, incompletely fused labioscrotal folds with increased rugosity and bilateral palpable gonads [Figure 1]. There was a single urogenital opening in the perineum, below the phallus. There was no hyper pigmentation of genitalia. Hernial sites showed no abnormality. Other systemic examination was essentially normal.
|Figure 1: Genitalia showed ambiguity as evidenced by microphallus, incompletely fused labioscrotal folds, and bilateral palpable gonads|
Click here to view
Investigations revealed hemoglobin of 10.0 g/dL, white blood cell count = 6600 cells/cumm. S. electrolytes showed hyponatremia, hyperkalemia, and hypochloremia (S. sodium = 103 mEq/L, S. potassium = 7-6 mEq/L, S. chloride = 87 mEq/L), blood pH 7.23, serum bicarbonate 8 mEq/L, glucose 39 mg/dL. In view of the vomiting, ambiguous genitalia, failure to thrive, and salt-wasting crisis, a suspicion of CAH was made. Blood for hormonal levels was drawn just after starting vigorous fluid replacement and correction of electrolyte abnormalities.
Serum testosterone was 0.39 ng/mL (normal- 3-12 ng/mL, no rise after human chorionic gonadotropin stimulation), progesterone - 0.74 ng/mL (normal - 0.13-1.26 ng/mL), dehydroepiandrosterone (DHEA) 527.22 μg/dL (normal - 133-440 μg/dL), 17-OHP 236.84 ng/mL (normal = <200 ng/mL), 17α-hydroxypregnenolone (Δ5 17-OHP) was 1160 ng/dL (normal < 10 ng/dL), serum androstenedione was >1000 ng/dL (90-460 ng/dL), morning cortisol 4.28 μg/dL (normal - 5-25 μg/dL), ACTH 52.16 pg/mL (reference value: 0-46 pg/mL). The Δ5 17-OHP/cortisol relation was 271, that is, above the proposed criteria for 3β-HSD deficiency diagnosis (≥94). Subsequently, the patient fully recovered and has shown normal weight and height gain and psychomotor development suitable for age.
Karyotype revealed 46XX genotype [Figure 2]. Abdominal imaging revealed streaky testes in labioscrotal folds, normal adrenals, and absence of mullerian structures or ovaries. To confirm 3β-HSD deficiency, we sequenced the HSD3B2 gene in the patient and family. Molecular analysis of the HSD3B2 gene from the affected case revealed the presence of the homozygous p.P222Q mutation, whereas his parents were heterozygous for it.
The baby was treated with fludrocortisone (100 mcg) and T. hydrocortisone 5 mg (1/4 th qid) and extra salt in feeds. The baby was also started on calcium gluconate and bicarbonate infusion for hyperkalemia. After 5 days of therapy, serum electrolytes were normal; the baby had no vomiting and had started putting on weight. Baby was discharged on hydrocortisone, fludrocortisone, and nutritional supplements of multi-vitamin syrup and syrup Vitamin D 400 IU per day.
On follow-up, 2 months later, vomiting has subsided, and the baby has adequate weight gain. Parents have been counseled about the sex. Surgical correction accordingly for the external genitalia has been advised, and the patient has been referred to the pediatric surgeon for the same.
| Discussion|| |
DSD are uncommon, but not rare. DSDs occur because of aberrations in balance of hormonal milieu, metabolic causes and chromosomal abnormalities. , About 2% of live births do have mild undervirilization in males or masculinization in females.  Ambiguous genitalia occurs with an incidence of 1 per 50,000-70,000.  Ambiguous genitalia is uncommon in a primary care pediatrician's practice, but their diagnosis and prompt treatment require urgent medical attention. Quickly establishing a definitive diagnosis and appropriate treatment plan will minimize medical, social, and psychological complications.
One of the most common cause of DSD with a salt-losing variety of ambiguous genitalia is CAH due to deficiency of 21-hydroxylase. HSD3B2 deficient CAH is an uncommon variant of CAH. It results from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, HSD3B2. ,
Like the other forms of CAH, suspicion of severe 3β-HSD CAH is usually raised by the appearance of ambiguous genitalia at birth or by the development of a salt-wasting crisis in the early part of life. The diagnosis is usually confirmed by the distinctive pattern of adrenal steroids: Elevated pregnenolone, 17-hydroxypregnenolone, DHEA, and renin. In clinical circumstances, this form of CAH has sometimes been difficult to distinguish from the more common 21-hydroxylase deficient CAH because of the 17-OHP elevation, or from simple premature adrenarche because of the DHEA elevation.
There is a wide spectrum of clinical presentations of 3β-HSD CAH, from mild to severe forms. The uncommon severe form, as in our case results from a complete loss of enzymatic activity and manifests itself in infancy as salt wasting due to the loss of mineralocorticoids.  This form of primary hypoadrenalism is the only form of CAH that can cause ambiguous genitalia in both genetic sexes.
The clinical diagnosis of 3β-HSD deficiency, in this case, was confirmed by the identification of the p.P222Q homozygous inactivating mutation in the HSD3B2 gene. Several mutations, including frameshift, nonsense, in-frame deletions, splicing, and missense mutation, have been described in the HSD3B2 gene in patients suffering from classical 3β-HSD deficiency. 
The diagnosis of ambiguous genitalia in a newborn infant is an emergency that can be difficult to manage, not only because of salt-wasting emergencies but also due to the importance of gender assignment.  Early, correct and complete diagnosis of DSD will provide the patient and family with a better understanding of the disorder. Genital reconstruction is necessary for the majority of patients with ambiguous genitalia, after the multidisciplinary team, in conjunction with the family, have decided on the appropriate gender assignment. 
A multidisciplinary approach but individualization of each case involving the obstetrician, neonatologist, pediatric surgeon, pediatric endocrinologist, geneticist, psychologist, and a social worker has to be done. To conclude, management of DSDs is a great challenge in our Indian population and requires expeditious workup, proper counseling, and appropriate assignment of sex. 
| Acknowledgments|| |
We wish to thank the Department of Endocrinology and Paediatric Surgery, Base Hospital, Delhi Cantt, New Delhi, India for their outstanding assistance.
| References|| |
Lambert SM, Vilain EJ, Kolon TF. A practical approach to ambiguous genitalia in the newborn period. Urol Clin North Am 2010;37:195-205.
Massanyi EZ, Dicarlo HN, Migeon CJ, Gearhart JP. Review and management of 46,XY disorders of sex development. J Pediatr Urol 2013;9:368-79.
Jaruratanasirikul S, Engchaun V. Management of children with disorders of sex development: 20-year experience in southern Thailand. World J Pediatr 2014;10:168-74.
Kulkarni KP, Panigrahi I, Das R, Kaur S, Marwaha RK. Pediatric disorders of sex development. Indian J Pediatr 2009;76:956-8.
Abu-Rustum RS, Chaaban M. Is 3-dimensional sonography useful in the prenatal diagnosis of ambiguous genitalia? J Ultrasound Med 2009;28:95-7.
Simard J, Moisan AM, Morel Y. Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency. Semin Reprod Med 2002;20:255-76.
Nordenström A, Forest MG, Wedell A. A case of 3beta-hydroxysteroid dehydrogenase type II (HSD3B2) deficiency picked up by neonatal screening for 21-hydroxylase deficiency: Difficulties and delay in etiologic diagnosis. Horm Res 2007;68:204-8.
Cravioto MD, Ulloa-Aguirre A, Bermudez JA, Herrera J, Lisker R, Mendez JP, et al.
A new inherited variant of the 3 beta-hydroxysteroid dehydrogenase-isomerase deficiency syndrome: Evidence for the existence of two isoenzymes. J Clin Endocrinol Metab 1986;63:360-7.
Rhéaume E, Simard J, Morel Y, Mebarki F, Zachmann M, Forest MG, et al.
Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene. Nat Genet 1992;1:239-45.
Baratz AB. Sex determination, differentiation, and identity. N Engl J Med 2004;350:2204-6.
Conte F, Grumbach M. Diagnosis and management of ambiguous external genitalia. Endocrinologist 2003;13:260-8.
Ahmed SF, Morrison S, Hughes IA. Intersex and gender assignment; the third way? Arch Dis Child 2004;89:847-50.
[Figure 1], [Figure 2]