• 46XY DSD
• NR5A1
• SF-1

Introduction
The NR5A1 gene (MIM 184757; 9q33.3) encodes steroidogenic factor 1 (SF1),
also known as adrenal 4-binding protein. SF1 is a 461-amino acid protein
belonging to the NR5A subfamily of nuclear receptors; it binds to specific DNA
sequences in target genes and regulates their transcription acting as key regulator
of endocrine function within the hypothalamic-pituitary-steroidogenic axis.
In humans, NR5A1 mutations have been reported in individuals with disorders (or
differences) of sex development (DSD). Variable clinical spectrum may be
associated with genetic variants of NR5A1 in both 46,XY and 46,XX individuals.
Objective
The objective of this thesis is to report on a group of Italian 46,XY people affected
by relatively new discovered DSD: NR5A1 (or SF-1) deficiency.
Patients and methods
An electronic worksheet was shared among the members of Italian DSD (It-DSD)
network to collect anonymized data on clinical, endocrine and genetic features of
Italian persons with 46,XY DSD due to NR5A1 genetic variants.
Results
A total of 29 patients with 46,XY DSD and NR5A1 genetic variants was collected
from 9 participating centers. At first observation, median age was 3.8 years (range
1 month - 22 years). The diagnosis of NR5A1 deficiency was done at a median age
of 10.2 years (range 0,1 – 34,5 years).
A higher percentage of large for gestational age (LGA) neonates were found in
these patients.
The diagnosis of NR5A1 deficiency was done at a median age of 10.2 years. Only
2 patients had NR5A1 deficiency as first diagnosis; other DSDs were firstly
diagnosed in the remaining patients.
Genital phenotype was variable, from female with mild clitoromegaly, partial
labial hypertrophy and/or inguinal hernia containing gonads, to predominantly
male with micropenis, cryptorchidism and/or hypospadias. At birth, female sex
was assigned in 18 cases and male sex in 10 ones. Gender was initially unassigned
in one newborn. In the end of follow-up, we have 18 females and 11 males.
Gonadectomy was performed in the majority of children assigned to female sex
(15/18); the testes were maintained in all the subjects assigned to male sex.
Histological data of the gonads were available for 13 subjects and showed varying
degrees of gonadal dysgenesis, while histology was negative for testicular cancer.
Hormone levels were below the mean in the youngest subgroups, while mean
testosterone values resulted above the mean in the adolescent group. In
adolescent/young adult group, mean ASI was above reference range (259 IU x
nmol x L-2; range 83.7 to 459 IU x nmol x L-2). Gonadotropin values were above
the normative range in a minority of patients during infancy and prepuberty, while
both LH and FSH were elevated in the majority of adolescents.
Only one homozygous mutation of NR5A1 gene was found. NR5A1 genetic
variants were detected in the coding exons from 2 to 7. Point mutations were
detected in 19 patients (83%), deletions in 3 patients (13%) and duplication
(c.691-699 dup CTGCAGCTG) in a single patient. Deletions of exons 5 and 6
were present in one patient. No clear correlation between genotype and phenotype
was found.
At last visit (median age 14.5 years), normal growth pattern was observed.
Conclusion
This series is the largest sample of people 46, XY with documented NR5A1
deficiency from a single European country.
Patients with DSD, having such a large phenotypic spectrum, should be
centralized towards reference centers to optimize outcome.
Finally, an accurate cancer risk estimation to guide gonadal fate should be
highlight in further longitudinal studies.