Isolated Growth Hormone Deficiency, Type Ii

A number sign (#) is used with this entry because of evidence that isolated growth hormone deficiency type II (IGHD2) is caused by heterozygous mutation in the GH1 gene (139250) on chromosome 17q23.

Description

Type II IGHD is an autosomal dominant disorder characterized by low but detectable levels of growth hormone (GH), variable height deficit and age at presentation, and good response to rhGH. Patients may show anterior pituitary hypoplasia on MRI (summary by Phillips and Cogan, 1994; Alatzoglou and Dattani, 2012).

Clinical Features

Phillips and Cogan (1994) referred to the autosomal dominant form of isolated growth hormone deficiency as IGHD II. They pointed out that the clinical severity varies considerably between kindreds and that affected patients respond well to GH treatment without the development of antibodies.

Merimee et al. (1969) and Tyson (1971) observed a family with affected persons in 4 generations. Dominant inheritance seems possible in the case of those patients who have isolated growth hormone deficiency but do not have insulinopenia as is found in most such cases. Unlike type I isolated growth hormone deficiency (see 262400), insulin responses to glucose and to arginine are usually greater than normal.

Tani et al. (1987) described 5 cases of isolated growth hormone deficiency in 3 successive generations. The 3 patients who were so studied had no abnormality of their growth hormone genes on Southern blot analysis. CT scans showed empty sella. Growth hormone was detectable in the plasma by radioimmunoassay but levels were clearly lower than in normal children, and significant increases were not obtained with the insulin tolerance test or with the arginine-TRH-LHRH triple loading test. Repeated injections of growth hormone releasing factor (GHRF; 139190) had no effect.

In a high proportion of patients with isolated growth hormone deficiency and multiple pituitary hormone deficiency, characteristic radiologic findings include (1) a small or absent anterior pituitary gland, (2) a small or truncated infundibulum, and (3) an ectopic posterior pituitary hyperintensity located at the base of the hypothalamus or inferior end of the truncated pituitary stalk. These findings have been attributed to a developmental defect, trauma, or ischemia at birth. Hamilton et al. (1998) described isolated growth deficiency in mother and son with characteristic findings on magnetic resonance imaging. The son also had a Chiari type I malformation and medial deviation of the carotid arteries secondary to a narrow skull base. Testing failed to identify a mutation in either the PIT1 gene (173110) or the growth hormone gene cluster. The authors interpreted the case as one of autosomal dominant defect in early development, lending support to the hypothesis that dysgenesis, rather than birth trauma, may cause a small anterior pituitary and ectopic posterior pituitary.

Inheritance

Numerous reports support autosomal dominant inheritance of a form of isolated growth hormone deficiency. Persons who appear to have had isolated growth hormone deficiency have been observed in successive generations. Selle (1920) is said (Warkany et al., 1961) to have described a kindred in which 'primordial dwarfism' was transmitted through 3 generations, 10 persons being affected. Multigeneration kindreds were included in the review of Rischbieth and Barrington (1912).

Dominant inheritance is a possible explanation for the findings in a family in which 2 dwarf parents with demonstrated isolated growth hormone deficiency have 3 offspring, 2 with dwarfism and 1 of normal stature (Rimoin et al., 1966). The father's condition may have been the result of new dominant mutation and he may have transmitted the condition to the 2 affected offspring.

Sheikholislam and Stempfel (1972) reported isolated GH deficiency in a man and 3 daughters and a son. Three other children were unaffected. Pedigree patterns consistent with dominant inheritance were reported also by Butenandt and Knorr (1970) and by Sadeghi-Nejad and Senior (1974). (The latter report concerned association with Rieger syndrome (180500).)

Poskitt and Rayner (1974) described 2 families, each with a father and son affected by isolated GH deficiency.

Rona and Tanner (1977) described an affected parent and 2 children with no known consanguinity.

Van Gelderen and van der Hoog (1981) reported isolated GH deficiency in 2 girls and their mother. Two maternal uncles, 135 cm tall, and the maternal grandmother were presumably affected also. The mother's height was 133 cm.

Cytogenetics

Schober et al. (1995) described growth hormone deficiency and empty sella in a 6-year-old girl with 18p monosomy. Good response to growth hormone treatment was observed. A rudimentary pituitary stalk was considered to underlie the hormone deficiency. The association of growth hormone deficiency and pituitary hypoplasia in 18p monosomy was also found by Artman et al. (1992). In addition to short stature, the craniofacial features of 18p monosomy may resemble those of Turner syndrome: round face, hypertelorism, flattened nasal bridge, and wide mouth with small upper lip. Various degrees of mental retardation have been observed.

Molecular Genetics

Most mutations leading to type II IGHD have been shown to affect the correct splicing of GH1, and in the majority of cases they are single base mutations within the first 6 nucleotides of intron 3. The result is the skipping of exon 3 and the production of the 17.5-kD isoform that exerts a dominant-negative effect on the secretion of the 22-kD molecule (summary by Alatzoglou and Dattani, 2012).

In affected members of a Turkish family segregating IGHD II, Phillips and Cogan (1994) identified a splice site mutation in the GH1 gene (IVS3+6T-C; 139250.0007).

Mullis et al. (2005) studied a total of 57 subjects with IGHD II belonging to 19 families with different splice site as well as missense mutations within the GH1 gene. The subjects presenting with the splice site mutation within the first 2 bp of intervening sequence 3 (139250.0009) leading to a skipping of exon 3 were more likely to present in the follow-up with other pituitary hormone deficiencies. In addition, although the patients with missense mutations had been reported to be less affected, a number of patients presenting with a missense GH form showed some pituitary hormone impairment. The development of multiple hormonal deficiencies is not age-dependent, and there is a clear variability in onset, severity, and progression, even within the same families. Mullis et al. (2005) concluded that the message of clinical importance from these studies is that the pituitary endocrine status of all such patients should continue to be monitored closely over the years because further hormonal deficiencies may evolve with time.

Shariat et al. (2008) studied a 4-generation family with IGHD II and identified a heterozygous missense mutation in the GH1 gene (EX3+1G-A; 139250.0025) in affected individuals. Functional analysis of this variant as well as G-T and G-C changes at the first nucleotide of exon 3 illustrated the multiple mechanisms by which changes in sequence can cause disease: splice site mutations, splicing enhancer function, messenger RNA decay, missense mutations, and nonsense mutations. The authors noted that for IGHD II, only exon skipping leads to production of the dominant-negative isoform, with increasing skipping correlating with increasing disease severity.