Triple A Syndrome in a Patient with Genetic Growth Hormone Insensitivity: Phenotypic Effects of Two Genetic Disorders

Abstract

Background: Primary growth hormone insensitivity (GHI) and triple A syndrome are rare autosomal recessive disorders. Case Report: The patient, a 12-year-old boy from consanguineous parents, was referred for short stature at the age of 7 years (height: -5.4 SD score). He had low serum insulin-like growth factor I (IGF-I) and IGF binding protein 3 and a blunted IGF-I response to recombinant human GH; molecular analysis of the GH receptor disclosed a homozygous A_-1→G_-1 at the 5′ pseudoexon 6Ψ splice site. Recombinant IGF-I therapy (mecasermin, Increlex®, twice daily) initiated at the age of 9 years resulted in an increase of height velocity (HV) from 4.0 to 9.5 cm/year. At the age of 10.5 years, he presented with asthenia, anorexia, weight loss, a decrease in HV and very low cortisol levels; adrenal insufficiency was confirmed and glucocorticoid therapy was initiated. Subsequent peripheral motor neuropathy, achalasia and alacrima raised the suspicion of triple A syndrome, which was confirmed by the presence of a homozygous R194X mutation in the AAAS gene. Conclusion: This unusual combination of diseases, to our knowledge, has not been reported to date. Although the patient responded to recombinant IGF-I therapy for GHI, we hypothesize that the treatment could have had an inhibitory effect on 11β-hydroxysteroid dehydrogenase type 1 activity, thereby reducing the availability of cortisol and precipitating adrenal insufficiency.

A Novel <b><i>GHR</i></b> Intronic Variant, <b><i>c.266+83G>T</i></b>, Activates a Cryptic 5′ Splice Site Causing Severe GHR Deficiency and Classical GH Insensitivity Syndrome

“…The classical GHI phenotype, severe primary IGF deficiency and profound growth retardation presentation by our patients was in contrast to patients carrying the c.618+792A>G variant [18,28,29] who, interestingly, had normal circulating GHBP concentrations. Identified in at least 8 unrelated consanguineous families, the c.618+792A>G mutation confers a broad spectrum of GHI phenotypes, with serum IGF-1 concentrations ranging from abnormally low to normal, and some patients having normal facial appearances [18,28,29].…”

“…Identified in at least 8 unrelated consanguineous families, the c.618+792A>G mutation confers a broad spectrum of GHI phenotypes, with serum IGF-1 concentrations ranging from abnormally low to normal, and some patients having normal facial appearances [18,28,29]. In these cases, the overall growth retardation was significantly less severe than for classical GHI cases, which would include the probands in the present report.…”

Genetic Analysis of GHR Should Contain Sequencing of All Coding Exons and Specific Intron Sequences, and Screening for Exon Deletions

“…In the past years, 14 other patients from 6 unrelated families with a pseudoexon 6 mutation of the GHR have been described [10,11,13]; 5 of these families were from Pakistani origin and 1 family was from Palestinian-Arab origin. Our family is from Surinam-Hindustan descent, so there may be a founder effect originating from the Indian subcontinent.…”

“…The clinical phenotype is broad, ranging from normal facial features to a typical Laron facies. Short stature is the most common presenting symptom and ranges from -3.3 to -6.0 SDS [10,11,13]. IGF-1 and IGFBP-3 levels are usually low or in the lower normal range.…”

“…Only 2 patients have been reported to have received rIGF-1 treatment [13]. Height velocity in the patient with the combined GHR and AAAS mutation increased from 4.0 to 9.5 cm/year in the first year, but decreased to 5.0 cm/year in the second year.…”