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).