Download Guide to DSD

Guide to Disorders of Sex Differentiation
XY Sex
Condition/Gene
Inheritance Prenatal Finding
Reversal
AIS (AR gene)
X-linked
recessive
Sensitivity
*not established prenatally
Considerations
Complete: male karyotype and
female on u/s
83-95% individuals with a clinical
diagnosis of complete AIS and CGD are
found to have a mut in AR
Most common
cause of isolated XY
disorder of sexual
differentiation
Partial: male karyotype and
female or ambiguous genitalia
on u/s
Male karyotype and female or
ambiguous genitalia on u/s
Milder phenotypes, sensitivity not well
established, likely <50%
Prenatal Dx
available at
GeneDx
Sequencing
5-α reductase
deficiency
(SRD5A2 gene)
AR
76% pts with clinical dx have 2
identifiable mutations in SRD5A2; 16%
had 1 identifiable mutation
XY sex reversal
with or without
adrenal failure
(NR5A1 gene
[SF1])
AD/AR
have been
reported
Male karyotype and female or
ambiguous genitalia on u/s
13-33% pts with 46,XY karyotype and
PGD or CGD and normal renal function
~12% pts with 46,XY gonadal
dysgenesis and adrenal failure
15% pts with hypospadias and
undescended testes
46,XY CGD or
PGD/ TestisDetermining
factor
(SRY gene)
Y-linked
Male karyotype and female or
ambiguous genitalia on u/s
20-30% in individuals with 46,XY CGD
(10-15% detectable by FISH/array)
(10-15% detected by sequencing)
Rare (<1%) in individuals with 46,XY
PGD
Founder mutations
in certain
populations (Turkey,
Brazil, Mexico,
Egypt, New Guinea)
More common with
sex reversal
Rare in ambiguous
genitalia
Known
familial
mutation
Sequencing
Known
familial
mutation
Whole
genome or
targeted array
Microdeletion/
Microduplication
syndromes
varies
NR0B1
gene
Male karyotype and female or
ambiguous genitalia on u/s
Up to 29% of individuals with XY DSD
have been identified with copy
number variants by array CGH
Duplications have been identified in 45% of individuals with 46,XY PGD or
Duplications in
NR0B1 result in
Whole
Guide to Disorders of Sex Differentiation
[DAX1]
X-linked
CGD
WNT4
gene
AD
Currently not well established
Campomelic
dysplasia
(SOX9 gene)
AD
Smith-Lemli-Opitz
(DHCR7 gene)
AR
Antley-Bixler
Syndrome [ABS]/
P450
Oxidoreductase
Deficiency
(POR gene)
AR
46,XY gonadal
dysgenesis with
minifascicular
neuropathy
(DHH gene)
AR
Male karyotype and female or
ambiguous genitalia and limb
shortening and/or bowing on
u/s
Male karyotype and female or
ambiguous genitalia and IUGR,
brain, cardiac, renal, or limb
malformation on u/s and/or
low MS-uE3 levels on maternal
serum screening
Male karyotype and ambiguous
genitalia and fixed flexion of
elbows, bowing of long bones,
hypoplastic midface, depressed
nasal bridge, brachycephaly,
and rocker-bottom feet on u/s
and/or low/undetectable MSuE3 levels on maternal serum
screening
Male karyotype and female
genitalia on u/s
90-95% individuals with clinical dx of
CD have mutation identifiable by
sequencing
5% have deletion identifiable by array
One or both mutations identified by
sequencing in 96% of individuals with
clinical and biochemically characterized
SLOS
Currently not well established:
In individuals with a clinical diagnosis of
ABS 19/32 (59%) had at least one
identifiable POR mutation, including
15/15 (100%) of individuals with
abnormal steroids and/or genitalia.
Currently not well established:
One study found homozygous DHH
mutations in 3 of 6 patients of
Mexican-Mestizo ancestry with 46,XY
CGD. Another study found DHH
46,XY DSD.
Sequence variants
cause X-linked
Adrenal Hypoplasia
Congenita
Duplications
involving WNT4 in
individuals with
46,XY DSD appears
to be rare
Rare in individuals
with sex reversal in
absence of skeletal
malformation
genome
chromosomal
microarray
Sequencing
Maternal virilization
can be seen during
pregnancy with
affected fetus
Known
familial
mutation
Full
Guide to Disorders of Sex Differentiation
17α-Hydroxylase
Deficiency
(CYP17A1 gene)
XX Sex
XX males/ SRYReversal positive 46,XX
testicular DSD
(SRY gene)
Antley-Bixler
Syndrome [ABS]/
P450
Oxidoreductase
Deficiency (POR
gene)
21-hydroxylase
deficiency (CAH)
(CYP21A2 gene)
Aromatase
Deficiency
(CYP19A1 gene)
AR
Male karyotype and female or
ambiguous genitalia on u/s.
Y-linked
Female karyotype and male or
ambiguous genitalia on u/s
AR
Female karyotype and
ambiguous genitalia and fixed
flexion of elbows, bowing of
long bones, hypoplastic
midface, depressed nasal
bridge, brachycephaly, and
rocker-bottom feet on u/s
and/or low/undetectable MSuE3 levels on maternal serum
screening
Female karyotype and
ambiguous genitalia on u/s
AR
AR
Female karyotype and
ambiguous genitalia on u/s
mutations in 1 in 4 patients with 46,XY
CGD and peripheral neuropathy. A
larger study found no DHH mutations in
96 individuals with 46,XY CGD and 48
individuals with 46,XY PGD
Two identifiable mutations identified in Founder mutations
nearly all patients with clinical dx of
in certain
17α-hydroxylase deficiency
populations (Brazil,
Canadian
Mennonites, Dutch
Freislanders,
Chinese)
80% individuals with 46,XX testicular
Rarely presents with
DSD have presence of SRY detectable
ambiguous genitalia
by FISH/microarray
Currently not well established:
In individuals with a clinical diagnosis of
ABS 19/32 (59%) had at least one
identifiable POR mutation, including
15/15 (100%) of individuals with
abnormal steroids and/or genitalia.
80-98% with a clinical dx of CHA have
mutations identifiable by sequence
analysis
Currently not well established
Maternal virilization
can be seen during
pregnancy with
affected fetus
sequencing
not available
prenatally
Known
familial
mutation only
Whole
genome or
targeted array
Sequencing
Known
familial
mutation
Vary rare disorder
Full
sequencing
not available
prenatally
Known
familial
mutation only
Guide to Disorders of Sex Differentiation
CGD= complete gonadal dysgenesis=46,XY sex reversal
PGD= partial gonadal dysgenesis=46,XY with ambiguous genitalia
DSD= disorder of sexual development=46,XY CGD and PGD combined/46,XX sex reversal or 46,XX with ambiguous genitalia