Patient 1
Patient 1 was born at 38 weeks gestation by repeat Cesarean section to a 33-year-old G2P1001 mother. Prenatal ultrasound detected a Dandy-Walker malformation, confirmed after birth with brain MRI. The remainder of the pregnancy was unremarkable. The family history was remarkable for a sister (patient 2) with an atrial septal defect (ASD) and clubfeet. The remainder of the family history was negative for birth defects, intellectual disability, and recurrent miscarriages. The mother and father are second cousins (their mothers are first cousins).
The patient’s birth weight was 3.78 kg (69thpercentile), length was 54.0 cm (93rd percentile), and Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. He had neonatal hypoglycemia, which resolved spontaneously within the first day of life, and feeding difficulties, which resolved by 6 months of age. A patent foramen ovale was identified.
At birth, the patient had ambiguous genitalia with a bifid scrotum. Specifically, he had a penoscrotal transposition with buried penis and prominent suprapubic fat pad. He also had ventral chordee, left-sided hydrocele, and a left inguinal hernia. The patient had a low luteinizing hormone (LH) and lower limits of normal follicle-stimulating hormone (FSH) in the newborn period. Testosterone and dihydrotestosterone levels were normal for age, but anti-Mullerian hormone was low for newborn males, suggesting normal Leydig cell function but abnormal Sertoli cell function. A renal ultrasound showed normal appearing kidneys bilaterally with no evidence of hydronephrosis. At 7 months of age, the patient had a penoplasty, scrotoplasty and repair of the left inguinal hernia and hydrocele.
The patient had both developmental and speech delay, He sat alone at approximately 5 months, crawled at 11 months, and was not walking independently at 16 months of age. Growth parameters at 16 months of age were 11.4 kg (53rd percentile) for weight, 78.6 cm (29th percentile) for length, and an OFC of 49 cm (87th percentile). Mildly dysmorphic features observed included short palpebral fissures with hypertelorism, cupped ears with overfolded helices, short nose, a smooth philtrum, full cheeks, and micrognathia. (Figure 1a). Other features noted were displaced nipples, tapered fingers, edema of the feet, and loose skin.
At age 9 years, he underwent an adenoidectomy and turbinate cauterization due to concerns for apnea. His growth parameters for height, weight and head circumference were at the 75th-90th percentile. He had moderate expressive and receptive language delays and received speech intervention, occupational, music, physical, and recreational therapies. He was diagnosed with ADHD, and is homeschooled, working at a 3rd grade level. At age 10 years 11 months, he is prepubescent. A testicular ultrasound revealed healthy appearing bilateral testes located within the scrotum without mass or concerning features. His gender identity remains male.
G-banded chromosome analysis, performed at birth, identified additional unknown material on 9p. Parental blood studies demonstrated that the patient’s father had a balanced reciprocal translocation between 3p and 9p written as 46,XY,t(3;9)(p25.1;p24.3). Based on paternal results, the patient’s karyotype was revised to 46,XY,der(9)t(3;9)(p25.1;p24.3)pat, resulting in partial 3p duplication and partial 9p deletion.
Chromosomal microarray analysis (CMA) identified a duplication at 3p26.3p25.1, approximately 13.5 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). Also identified were segments of copy-neutral absence of heterozygosity (AOH) across multiple chromosomes encompassing around 2.2% of the genome (Figure S2).