Corticosteroid-Binding Globulin Deficiency
A number sign (#) is used with this entry because of evidence that corticosteroid-binding globulin (CBG) deficiency can be caused by heterozygous or homozygous mutation in the SERPINA6 gene (122500) on chromosome 14q32.
Clinical FeaturesDoe et al. (1965) found decreased levels of serum corticosteroid-binding globulin in 8 persons in 3 generations of a family. Male and females were affected similarly. There was no male-to-male transmission.
DeMoor et al. (1967) found a bimodal distribution of CBG levels in males but not in females, and the fathers of males with low levels showed normal levels. The authors felt that X-linked inheritance best accounted for the findings.
Emptoz-Bonneton et al. (2000) reported a 43-year-old woman who was referred for chronic asthenia, hypotension, and depression. Biochemical studies showed decreased serum CBG and very low serum cortisol concentration.
Torpy et al. (2001) reported an Italian American family in which many individuals had decreased plasma immunoreactive CBG associated with hypotension and fatigue. Many had idiopathic chronic fatigue and 5 cases met the Centers for Disease Control criteria for chronic fatigue syndrome. The authors concluded that, as idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of CBG may be pathogenic.
Buss et al. (2007) reported a 22-year-old man with severe muscle fatigue mostly experienced after stressful events. He had increased free urinary cortisol, increased salivary free cortisol in the morning, and high saliva cortisol, despite normal serum cortisol concentration after a psychosocial stress test. Serum CBG was decreased. He showed a blunted serum cortisol increase after ACTH challenge. Blood pressure was normal.
Elevated Corticosteroid-Binding Globulin
Elevated CBG was found in a brother and sister by Lohrenz et al. (1968). Neither sib had children, and the mother, the only surviving parent, had normal CBG levels.
Coolens and Heyns (1989) found unexplained high serum CBG concentrations repeatedly in 2 apparently healthy sisters who were not pregnant and not taking exogenous estrogens. One had substantial variation in serum CBG and sex hormone-binding globulin concentrations during the menstrual cycle, which paralleled the normal cyclic changes in serum estradiol. The other woman was postmenopausal and had a high serum CBG despite low serum estradiol levels. Coolens and Heyns (1989) speculated that these women had an inherited abnormality in CBG production. The authors noted that the practical importance of this condition was that a very high morning serum cortisol concentration could lead to confusion with Cushing syndrome.
Molecular GeneticsVan Baelen et al. (1982, 1993) identified a variation in the CBG gene (L93H; 122500.0001), referred to as 'transcortin Leuven,' in 3 unrelated individuals from a population study. Family study of 1 of the individuals showed transmission of the allele; 2 children were homozygous for the variant. Individuals who were heterozygous or homozygous for the L93H protein had normal levels of serum transcortin and evening cortisol levels. Functional analysis showed that the L93H protein had decreased cortisol-binding affinity, reflecting a functional deficiency of the protein. One heterozygote in the family and 2 unrelated heterozygotes identified in the population study had arterial hypertension.
In a 43-year-old woman with CBG deficiency Emptoz-Bonneton et al. (2000) identified a homozygous substitution in the CBG gene (D367N; 122500.0002), referred to as 'CBG Lyon.'
In affected members of an Italian-Australian family with CBG deficiency, Torpy et al. (2001) identified a null mutation in the SERPINA6 gene (122500.0003). The CBG Lyon variation segregated independently in the same kindred. Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without CBG mutations. Plasma immunoreactive CBG was undetectable in null homozygotes, and mean CBG levels were reduced by approximately 50% in null heterozygotes. Among 19 adults with the null mutation, 54% had a systolic blood pressure below the third percentile. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygotes (86%) and in 2 of 3 null homozygotes.
In a 22-year-old man with severe muscle fatigue associated with stress, Buss et al. (2007) identified a de novo heterozygous D367N mutation in the SERPINA6 gene. The authors postulated that in some cases CBG deficiency may act as an autosomal dominant disorder with incomplete penetrance, although a second pathogenic mutation could not be excluded in this case.