ClinVar Genomic variation as it relates to human health

Gonadal dysgenesis (present) , Bilateral cryptorchidism (present) , Penoscrotal hypospadias (present) , Decreased testicular size (present) , Elevated circulating follicle stimulating hormone level (present) , Elevated circulating luteinizing hormone level (present) , Non-obstructive azoospermia (present) (less)

In each of 2 separate families, Wu et al. (1998) showed that 3 sibs with combined pituitary hormone deficiency (CPHD2; 262600) carried a 2-bp deletion (301A and 302G) leading to a frameshift in the coding sequence starting at codon 101 and premature termination at codon 109. The truncation resulted in the loss of the DNA-binding homeodomain and the C-terminal transactivation domain of PROP1. Cogan et al. (1998) determined the frequency of the 301delAG mutation in exon 2 of PROP1 in 10 independently ascertained combined pituitary hormone deficiency (CPHD) kindreds and 21 sporadic cases of CPHD from 8 different countries. They found that 55% (11 of 20) of the PROP1 alleles were 301delAG in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles in the 21 sporadic cases were 301delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given thyrotropin-releasing hormone stimulation tests) was 50% (3 of 6) in the CPHD cases with pituitary defects, and 0% (0 of 34) in the CPHD cases with hypothalamic defects. Using whole genome radiation hybrid analysis, they localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. The authors concluded that analysis of this marker in affected subjects with the 301delAG mutation suggests that rather than being inherited from a common founder, 301delAG may be a recurring mutation. In 2 unrelated females with CPHD, Mendonca et al. (1999) identified homozygosity for the 301AG deletion in the PROP1 gene. MRI findings changed over time in these patients, and 1 had partial cortisol deficiency. The authors concluded that a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced T1 signal on MRI suggests PROP1 deficiency; that pituitary morphology can change during follow-up of patients with PROP1 mutations; and that hormonal deficiencies associated with PROP1 mutations can include the adrenal axis. In 10 CPHD patients from a large Brazilian kindred, 9 of whom were born of consanguineous marriages, Pernasetti et al. (2000) identified homozygosity for the 301AG deletion in PROP1. The authors observed ACTH/cortisol insufficiency in 5 of 6 of the older patients and in one 11-year-old patient, and suggested that the phenotype of this mutation includes late-onset adrenal insufficiency. Riepe et al. (2001) found this mutation in compound heterozygosity with 150delA (601538.0008) in 2 brothers with typical manifestations of PROP1 deficiency. The 301-302delAG frameshift mutation was found in homozygous state as the cause of the CPHD in the Hutterite cases reported by McKusick and Rimoin (1967) (Mosely et al., 2002). In 3 adult sibs, aged 18 to 25 years, with short stature, hypothyroidism, and lack of pubertal maturation, Lee et al. (2004) identified homozygosity for the 301AG deletion in PROP1. All 3 patients responded with a dramatic increase in linear growth to treatment with GH and thyroid replacement administered prior to beginning sex steroid replacement therapy. (less)

Abnormal circulating carnitine concentration (present) , Intellectual disability (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Autism (present) , Seizure (present) , Male hypogonadism (present) , Short stature (present) , Infantile muscular hypotonia (present) , Abnormal cheek morphology (present) , Abnormal jaw morphology (present) , Wide mouth (present) , Widely spaced teeth (present) (less)