Gonadal Dysgenesis, Dysmorphic Facies, Retinal Dystrophy, And Myopathy

A number sign (#) is used with this entry because of evidence that gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is caused by homozygous mutation in the PPP2R3C gene (615902) on chromosome 14q13.

Heterozygous PPP2R3C mutations in males cause teratozoospermia with reduced fertility (SPGF36; 618420).

Description

GDRM is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, including low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay (Guran et al., 2019).

Clinical Features

Guran et al. (2019) reported 4 unrelated 46,XY females from consanguineous Turkish families with syndromic complete gonadal dysgenesis. The genital phenotype was female with hypoplastic labia majora; uterus was present in 3 patients and a primitive bicornuate uterus was detected in the fourth patient. All 4 exhibited similar facial dysmorphism, with flat face, sparse arched eyebrows, epicanthal folds, beaked nose with hypoplastic alae nasi, long smooth philtrum, thin lips with narrow mouth opening, and low-set, posteriorly rotated ears with overfolded helix. They had unruly hair with frontal upsweep and unusual hair whorls, and skin was dry and scaly. All 4 had lacrimal puncta hypoplasia and rod-cone dystrophy. Of 3 patients who had auditory testing, 2 showed sensorineural hearing loss. All exhibited severe myopathy with thick, stiff muscles; patients 2 and 3 underwent electromyography that revealed severe diffuse myopathy. Skeletal findings included short stature, delayed bone age, and limited elbow extension, and all 4 exhibited neuromotor delay. Patients 2 and 4 underwent gonadectomy; histologic analysis showed few to no Leydig cells and peripherally located Mullerian-like tubular structures in loose connective tissue containing vessels and peripheral nerve bundles. Patient 3 was a 19-year-old woman who had no gonads seen on laparoscopy at age 13.75 years and was given estrogen replacement therapy starting at age 14; she had Tanner stage 2 breast development at age 14.5, Tanner stage 2 pubic hair at age 17.5, and underwent menarche at age 18. All of the families had a history of multiple infertile couples, and semen analysis in 3 of the probands' fathers revealed teratozoospermia (see SPGF36; 618420). The fourth father did not undergo testing, and other relatives were unavailable for testing. One heterozygous mother reported oligomenorrhea and hypomenorrhea with normal pelvic ultrasound, and another mother underwent menopause at age 44 years.

Molecular Genetics

In 4 unrelated 46,XY females from consanguineous Turkish families with syndromic complete gonadal dysgenesis, Guran et al. (2019) identified homozygosity for 3 different missense mutations in the PPP2R3C gene (615902.0001-615902.0003) that segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility (SPGF36).