At 4.5 years old, the child's height and weight were greater than 95th percentile, with weight disproportionately larger than height (Figure 2). His head circumference was at 90th percentile. He had a short forehead, well formed ears with fleshy lobes, a prominent brow, and a small dimpled chin. The obesity was associated with striae and inverted nipples. He had bridged palmar creases bilaterally, fifth finger clinodactyly on the left hand, and an increased space between the first and second toes.
At 4.5 years of age, the patient's bone age was 6.5 to 7 years, which is more than 2 standard deviations above the mean for his age. At 10 years of age, he had some pubic and axillary hair. His penis appeared small upon examination at both 10 and 15 years of age. At 15 years of age, the patient's height was 180.7 centimeters (90th percentile), weight was 150.8 kilograms (>97th percentile), and head circumference was 58 centimeters (75th-90th percentile). The BMI was 46.2, which is well above 99th percentile. Hormone studies were not available.
There was a family history of obesity, but not tall stature. The patient's father's BMI was 43.4 (obese), and his mother's BMI was 41 (obese). The patient's older brother's BMI was 26.2 (overweight). The patient's brother reportedly met his early developmental milestones appropriately. Subsequently, the brother had difficulties with speech, reading, and memory processing but was able to progress through school with assistance.
Genetic investigations including methylation studies for Prader Willi syndrome and Southern Blot for FMR1 for the patient were normal. Karyotype results were 46,XY,del(18)(q21.32q21.32). Sequencing of the MCR4 gene did not detect any mutations. A CGH microarray was undertaken to further define the patient's deletion.
Microarray evaluation using a 180k CGH microarray platform (hg19) gave a result of arr[hg19] 1p13.3 (109,336,197-109,779,618) x 3; 18q21.32q22.1 (56,201,352-62,696,664) x 1. The 0.463 Mb gain at 1p13.3 was described as a variant of uncertain significance and included the following genes: STBP3, AKNAD1, GPSM2, CLCC1, WDR47, TAF13, TMEM167B, SCARNA2, C1orf194, KIAA1324, SARS, and CELSR2. The 6.46 Mb loss at 18q is unique in size and location and includes the following genes: SERPINB3,  MC4R , PMAIP1, SERPINB5, VPS4B, SERPINB2,  MALT1, BCL2, LMAN1 , SCCHC2, PHLPP1, KDSR, SERPINB13, SERPINB10, HMSD, SEPRINB8,  SERPINB7 , SERPINB11,  TNFRSF11A , SERPINB4, SERPINB12, KIAA1468,  RAX , CPLX4, ALPK2, SEC11C, ZNF532,  CCB3E1 , GRP, CDH20, RNF152, and PIGN. Of the preceding list, the OMIM morbid disease genes are in bold. Deletion of MALT1, LMAN1, SERPINB7, TNFRSF11A, RAX, CCB3E1, and PIGN was not expected to have an effect on the patient as loss of function mutations need to be present in both copies of these genes in order to produce a disease state. Heterozygous mutations in Bcl-2 in mice have been shown to produce manic behavior, although this was not seen in our patient. Parental testing revealed that the 18q deletion was de novo. The patient's mother also had the 1p13.3 duplication.
Physical activity and diet management were recommended to manage the patient's obesity. He participated in a gym class and was counseled to minimize his excessive intake of sugar and unhealthy foods. In addition, the patient's family doctor was advised to monitor the patient for complications of obesity, including hyperinsulinemia, diabetes, and heart disease.