SAT-290 Expanded Phenotype Associated with RNF135 Intragenic Deletion in a Girl with Peripheral Precocious Puberty

Abstract

Introduction: RNF135 gene is located within the 17q11.2 region and is often deleted in the NF1 contiguous microdeletion syndrome. Six individuals with suspected pathogenic mutations of RNF135 have been described with similar phenotypes including facial dysmorphism (downslanted palpebral fissures, elongated philtrum, broad nasal tip, thin upper lip, broad forehead), macrocephaly, tall stature, overgrowth, and learning disabilities. We present the first reported case of a patient with RNF135 intragenic deletion and precocious puberty. Clinical Case: Patient had ambiguous genitalia at birth, suspicious for CAH. Laboratory evaluation was normal. At age 2, she presented with breast and pubic hair development over the previous year. Leuprolide stimulation test was not consistent with central precocious puberty. Pelvic ultrasound revealed a paraovarian cyst that was drained at age 4 and pubertal development stabilized. At age 6, had progression of puberty with Tanner III breasts. MRI pelvis showed a large cyst of the left ovary and a post pubertal appearing uterus. Patient underwent left oophorectomy for numerous ovarian cysts and concern for progression of precocious puberty. Pathology showed a serous cystadenoma and pubertal ovary. At age 7 years 5 months, she had torsion of the right ovary and underwent laproscopic detorsion. Biopsy showed extensively hemorrhagic tissue with foci of ovarian stroma. Pubertal development was stable until age 7 years 10 months, when she presented with Tanner IV breasts and Tanner II pubic hair. MRI pelvis showed a multicystic right ovary with follicles. Since age 2, patient had tall stature, with height Z score ranging 3.45-4.47. She was diagnosed with focal epilepsy at age 3.5 years and had a PDA that was coiled at age 4. At age 7, chromosomal microarray showed an 88 base pair deletion at chromosome 17q11.2, including part of the RNF135 gene. Patient has dysmorphic facial features, including hypertelorism, upslanted palpebral fissures, bilateral epicanthal folds, flat nasal bridge, malar hypoplasia, high arched palate. Other dysmorphic body features include dolichocephaly and sandal gap between toes 1 and 2. Patient has fine motor, gross motor, and speech delays. Conclusion: Mutations in the RNF135 gene are rare, with phenotypes only described in 6 individuals to date. Our patient exhibits many phenotypic features seen in described patients with pathogenic variants in this gene, including dysmorphic facial features, developmental delay, and tall stature. This is the first reported case of a patient with RNF135 intragenic deletion presenting with peripheral precocious puberty, cystic ovaries, and focal epilepsy. This case describes several new clinical features that are thought to be associated with a rare RNF135-related overgrowth syndrome.