Patient 2
Patient 2 (sister to patient 1) was born at term by Cesarean section due
to large size and posterior positioning. The pregnancy was without
complications. Birth weight was 3.94 kg (87thpercentile) and birth length was 48.9 cm (43rdpercentile). Hypoglycemia developed shortly after birth, which resolved
spontaneously. She had bilateral talipes equinovarus and a
moderate-sized ASD noted by echocardiogram.
A chromosome study of Patient 2 demonstrated the same karyotype as her
brother, 46,XY,der(9)t(3;9)(p25.1;p24.3)pat. However, she had
normal-appearing female external genitalia. A renal ultrasound was
normal, and a pelvic ultrasound initially appeared normal with both
ovaries and a uterus present. Gonadotropins measured at 2 years 8 months
demonstrated her LH was normal but FSH was markedly elevated, suggesting
gonadal dysgenesis and primary ovarian dysfunction. Laparoscopy showed a
normal uterus and Fallopian tubes. The ovaries appeared normal except
for a right cystic structure. The patient had a bilateral gonadectomy.
Pathology reports of the left gonad revealed a streak testis containing
a gonadoblastoma while the right gonad was an ovotestis.
The patient had developmental delays, especially with gross motor and
language skills. She walked at 20 months and said her first words at 18
months. At 3 years 2 months, her vocabulary consisted of reportedly more
than 100 single words and she was able to use two-word phrases.
The patient’s growth parameters at 3 years 5 months of age were 15.4 kg
(64th centile) for weight, 98 cm
(56th centile) for height, and she had an OFC of 51.2
cm (80th centile). At age 11 years, her growth
parameters were at 75th-90thpercentiles for height, weight and head circumference. Dysmorphic
features included brachycephaly, broad forehead, short nasal bridge, and
hypoplastic ala nasi. Percutaneous closure of her ASD was performed and
she has remained asymptomatic. On endocrine evaluation at age 11 year 7
months, her breasts were at Tanner stage I and pubic hair was Tanner
stage III. She began treatment for hypergonadotropic hypogonadism with
an estradiol patch at 12.5 mcg twice weekly. Her bone age was concordant
with her chronological age of between 10 and 11 years. An exam at age 13
years 8 months, noted Tanner stage III breasts and Tanner stage IV pubic
hair. She has not yet had menarche. Her gender identity remains female.
Developmentally, the patient was functioning with moderate cognitive
delays and severe language delay. She was receiving speech,
occupational, and recreational therapies. She has been homeschooled and
is performing near the 4th grade level.
Similarly, a CMA showed a duplication at 3p26.3p25.1, approximately
13.46 Mb in size involving 55 OMIM genes (chr3:61,891-13,562,132, hg19
coordinates) and a deletion at 9p24.3, approximately 1.17 Mb in size
involving 5 OMIM genes (chr9:203,861-1,373,611, hg19 coordinates; Figure
1c). The microarray also identified segments of copy-neutral AOH across
multiple chromosomes encompassing around 3.8% of the genome (Figure
S2).