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Another Cause of Primary IGF Deficiency

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Primary insulin-like growth-factor deficiency (PIGFD), abnormally low levels of IGF-I despite normal or elevated levels of growth hormone (GH), has been attributed to mutations in 4 genes to date: GHR, IGF1, STAT5b, and IGFALS. IGFALS encodes the acid-labile subunit (ALS) of the ternary complex, also under GH control. Fofanova-Gambetti et al reported 2 patients with 3 novel mutations in IGFALS, plus another 2 patients in the amendment while the paper was in press, to add to the currently published tally of 5 patients from 3 families harboring 4 different mutations. Of note, in contrast to patients with mutations of the other PIGFD genes, all patients with IGFALS mutations presented with modest short stature (height z-scores above –3 SD).

Previously published patients:

Case 1: A boy aged 14.6 years from Argentina with a height z-score of –2.05 SD and homozygous IGFALS mutation1338delG (E35fsX120), in the amino terminal flanking region.¹Case 2: A Turkish boy aged 12.1 years with a height z-score of –2.9 SD and homozygous IGFALS D440N missense mutation in the 17^th leucine-rich repeat (LRR) domain.²Cases 3-5: Three Norwegian/German siblings (2 male, 1 female) aged 15.3 to 19.6 years, with height z-scores of –0.5 to –2.0 SD and compound heterozygous C540R/583_591dup9 IGFALS mutations in the cystein-rich region of the carboxy terminus and the 7th LRR domain, respectively.³

Currently reported patients:

Case 1: A boy of 6.7 years of Mayan origin with a height z-score of –2.91 SD, delayed bone age (5.5 years) and homozygous IGFALS 1308_1316 dup9 mutation in the 17^th LRR domain. GH treatment began at the age of 8.5 years and was discontinued 1 year later due to development of nonalcoholic steatotic hepatitis. The patient’s transaminase levels continued to climb when he was off treatment, however they subsequently returned to normal. GH therapy was tried again from age 10 years for another 2 years. Despite increasing doses of GH, he failed to improve his growth velocity or normalize his IGF-I and IGF binding protein (IGFBP)-3 levels. During this time, at the chronological age of 10.5 years, he initiated spontaneous puberty and was started on LH-RH analogue therapy to preserve growth potential while on GH. At age 12 years, he was switched from GH to IGF-I therapy.
Case 2: A girl aged 4.1 years of Eastern European Jewish/Icelandic-Western European ethnic origin with a height z-score of –2.14 SD, bone age consistent to her chronologic age, and compound heterozygous IGFALS C60S/L244F missense mutations in the 1^st and 9^th LRR domains, respectively. She started GH treatment at age 4.4 years, increasing her height z-score in 13 months to –1.67 SD; IGF-I and IGFBP-3 levels nonetheless remained abnormally low, and ALS was undetectable.

Patients reported in the amendment:

Case 1: An Indian/Pakistani boy aged 15.2 years with a height z-score of –3.17 SD, delayed bone age (11 years), sexual infantilism and homozygous IGFALS L134Q missense mutations in the 4th LRR domain. His parents, both heterozygous carriers, had normal heights (–0.09 and –1.35 SDS).
Case 2: An Ashkenazi Jewish boy aged 12.7 years with a height z-score of –2.87 SD, bone age of 11.5 years, sexual infantilism and compound heterozygous IGFALS P73L/L241P missense mutations in the 1^st and 8^th–9^th LRR domains, respectively. His parents, both heterozygous carriers of one of the mutations, had normal heights (–1.68 and +0.85 SDS).

ALS protein, a member of the LRR superfamily of proteins involved in protein-protein interactions, contains 20 LRR domains that form a donut shape with a closed structure. The LRRs contain b-strands that form sheets inside the donut, and a-helices that flank the structure’s outer circumference. This paper highlights the ethnic and genetic heterogeneity of IGFALS mutations that are pathogenic in causing PIGFD and modest short stature that responds poorly to GH therapy. Although GH can induce IGF-I and IGFBP-3 production, without ALS, circulating levels of the growth factor are not sustained. This is a nice in vivo illustration of the importance of the ternary complex in prolonging the circulating half-life, and hence activity, of IGF-I.

Fofanova-Gambetti OV, Hwa V, Kirsch S, et al. Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins. Horm Res. 2009;71:100-110.

Editor’s Comment

Genotyping of the parents of Girl #2 in this paper was not available. The authors hypothesized that her mutations must be in the compound heterozygous state because her ALS protein was undetectable; had her mutations occurred in cis, then her wild-type allele would be expected to produce wild-type ALS that should have been detected, as was the case for the carrier parent of the Turkish boy with a homozygous missense mutation.² Another possibility is that the double mutations in cis so altered the ALS protein product that it functioned as a dominant negative, tying up the wild-type ALS in the ER or Golgi and preventing its secretion. This second hypothesis would require that one of the parents similarly carry the dominant negative in cis mutations, have undetectable ALS, and be affected. The father’s height z-score was +0.30 SD while the mother’s was –2.13 SD. Since one of the main teaching points of this paper is that ALS mutations cause PIGFD with only modest short stature, perhaps the mother is affected like her daughter?

Adda Grimberg, MD

References - (linked to )

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Last Updated: 6/12/2009