1. A Unique Case of Lamotrigine Induced Disorder of Sexual Differentiation
Satyam Chakraborty, Anirban Sinha, Animesh Maiti, Biplab Mandal, Ravindra Shukla
Lakshmi Dey, Ashish Kumar Basu
Department of Endocrinology & Metabolism, Medical College and Hospital, Kolkata, India
INTRODUCTION
PERTINENT LAB EXAMINATIONS
Undervirilized Phallus with ill Formed Glans
DISCUSSION
Disorders of sexual differentiation (DSD) are in itself rare entities but in the past 15 years cases of anomalies of male sexual differentiation are on the rise.(1)
Notwithstandingly, they carry significant social stigma & parental anxiety, their exact hormonal cause in many cases remain obscure due to the lack of adequate investigational facilities in India.
We report a case of 46XY DSD child whose in-utero development was probably interfered with the maternal intake of Lamotrigine
Usually infants with 5 α-reductase deficiency have more severe genital ambiguity, history of consanguineous marriage in parents which is not seen in our case.
Differentiation between 5 α- reductase deficiency and PAIS (partial androgen insensitivity syndrome) is very difficult in infancy though infants with PAIS usually have normal T: DHT ratio (i.e. around 6.1) (9).
In most of the cases of 5α reductase deficiency, the cause remain unknown. In our case, we went further to explore the role of any endocrine disruptors as there was a history of antenatal exposure of an antiepileptic drug lamotrigine to the mother. We searched the effects of lamotrigine in web based literatures & its effect on the foetus. Hypospadias has been reported in significant number of cases.
According to the Lamotrigine Pregnancy Registry Final Report (6), there were significant numbers of hypospadias reported in male new borns (5), which could well be an effect of male under-androgenisation.
Fluck et.al in 2005 precisely pointed out that there was significant inhibition of several enzymes of the steroid bio-synthetic pathway viz.17-alpha hydroxylase-17,20-lyase & 3-beta hydroxy steroid dehydrogenase type 2 by lamotrigine
USG: Phallus & Urethra
CASE REPORT
A 1 year old child born of non-consanguineous marriage presented to us with genital ambiguity noted since birth.
The baby was born of full term normal delivery (3.6 kilogram) preceeded by an uneventful antenatal period excepting the fact that the mother was suffering from seizure disorder & was on lamotrigine 150 mg/day during pregnancy. No episode of seizure during the antenatal period and no history of maternal virilization during pregnancy
History suggestive of global developmental delay since birth.
The child had a length of 81.5 cm (> 97th percentile for age), a weight of 12 kg (> 95th percentile), a pulse of 122/ min & a blood pressure of 100 /70 (the 50th& 90th percentile for age respectively. No apparent skeletal defect was noted.
RESULTS
USG: Right & Left Testis
From the aforementioned data the serum testosterone: androstenedione ratio was found to be which disprove 17-Beta-Hydroxy steroid dehydrogenase deficiency.
The ratio of testosterone to dihydrotestosterone (T:DHT) was calculated as 21.5.
The definitive diagnosis of 5-Alpha Reductase type 2 deficiency in post pubertal male requires a ratio of 35 but it has been mentioned in medical literature that in the neonatal period any ratio greater than 8.5 may point to 5-alpha Reductase Deficiency & in infants the ratio typically exceeds 10 (4).
Thus it suggests our diagnosis of 5-alpha reductase type 2 deficiency.
Limitations: Urinary ratio of tetrahydrocortisol to allotetrahydrocortisol and assay of 5 alpha reductase activity in scrotal skin fibroblasts not performed due to limited resources
CONCLUSION
Our case probably for the first time throws light on the possibility of lamotrigine as an endocrine disruptor causing ambiguous genitalia because of an inhibitory impact on the enzymes of androgen biosynthetic pathway, perhaps 5-α alpha reductase enzyme also.
USG: Absence of Prostratic Tissue
FURTHER RESEARCH
GENITAL EXAMINATION
Few issues still remain unsolved about the developmental delay in the child. We performed a MRI scan of the brain & discovered significant amount of cortical atrophy with subdural hygroma. Anti-epileptics use during pregnancy may cause impairment of fine motor skills in off-springs, and has been well documented in the literature but whether cortical atrophy in our case may be attributed to the use of lamotrigine is a matter of further research. At the same time the role of adequate amount dihydrotestosterone in the development of male brain, lack of which may cause cortical atrophy, also needs to be thoroughly investigated
Under androgenized male genitalia in the form of labio-scrotal folds with mild pigmentation & rugosity which contained palpable gonads bilaterally, the volume being around 1 ml each.
Phallus length of 2.5 cm & diameter of 1 cm [age appropriate normal value being 1.1± 0.2cms2)]
Urethral orifice was present at the base of the phallus and the external masculinization score was 3/12. Testes were found in the labioscrotal fold which corroborates our clinical findings.
Gonadal Volume: Predus Orchidometer
REFERENCES
1.Environ Res. 2006; 100(1): J Pediatr.1975; 86(3): Horm Res Paediatr 2010; 74: Clinical Gynecologic Endocrinology and Infertility. 8th ed. Lipincott Williams & Wilkins; 2011: Archives of Disease in Childhood 1992; 67: Pregnancyregistry.gsk.com/documents/lam_spring_2010_final_report.pdf 7 .Epilepsia 2005; 46(3):