Global Developmental Delay, Lung Cysts, Overgrowth, And Wilms Tumor

A number sign (#) is used with this entry because of evidence that a syndrome of global developmental delay, lung cysts, overgrowth, and Wilms tumor (GLOW) is caused by postzygotic mutation, resulting in somatic mosaicism, in the DICER1 gene (606241) on chromosome 14q31.

Clinical Features

Klein et al. (2014) described 2 unrelated individuals with a unique association of congenital nephromegaly, bilateral Wilms tumor, somatic overgrowth, developmental delay, macrocephaly, and bilateral lung cysts. The first patient was a 9-month-old boy with macrosomia and large kidneys that had been noted prenatally. Birth weight was greater than the 98th percentile. Bilateral lung cysts as well as multiple small renal cysts were present. He had persistent macrocephaly, although weight and length dropped to the 90th percentile. At 9 months of age he could not roll over and had weak muscle tone. Wilms tumor prompted left kidney removal at 9 months. Kidney histology showed various abnormalities. At age 18 months, brain MRI showed enlarged lateral and third ventricles. Dysmorphic facial features included frontal bossing, a large anterior fontanel, slight hypertelorism, anteverted nares, flat nasal bridge, and slight micrognathia. At 28 months, he presented with dimples on the sides of his ankles, as well as fat pads on the dorsa of feet and toes and pronounced plantar creases on both sides. Other dysmorphic physical findings included large protuberant abdomen, pectus excavatum, kyphosis, and a sacral dimple. At age 5 years, he was diagnosed with Wilms tumor of the contralateral kidney as well as autism. The second patient was a boy who presented with global developmental delay and macrocephaly with normal head CT scan. At age 14 months he was not crawling or babbling. Birth weight was at the 15th percentile, but growth parameters had increased to greater than the 98th percentile for weight and head circumference and 75th to 80th percentile for length. At age 18 months he developed a large Wilms tumor for which nephrectomy was performed. Chest CT scan at 21 months showed multiple bilateral lung cysts. At 30 months of age there was tumor recurrence to the paraspinal area, spleen, contralateral kidney, and lungs, which was confirmed to be Wilms tumor by biopsy of the paraspinal mass. Dysmorphic facial features included depressed nasal bridge, left ear pit, frontal bossing, and hypertelorism.

Molecular Genetics

In 2 unrelated patients with global developmental delay, overgrowth, bilateral cystic lung lesions, and Wilms tumor, Klein et al. (2014) detected 2 missense mutations in the DICER1 gene (606241.0013 and 606241.0014) present in the mosaic state. Tissue abundance of the mutated DICER DNA ranged from 21 to 37% in patient 1 and 28 to 47% in patient 2 in blood, tumor, and unaffected kidney samples.