A Tunisian Patient with Two Rare Syndromes: Triple A Syndrome and Congenital Hypogonadotropic Hypogonadism

Abstract

Background/Aims: The coexistence of triple A syndrome (AAAS) and congenital hypogonadotropic hypogonadism (CHH) has so far not been reported in the literature. This study aimed to characterize at the clinical and genetic level one patient presenting an association of AAAS and CHH in order to identify causal mutations. Methods: Clinical and endocrinal investigations were performed and followed by mutational screening of candidate genes. Results: At the age of 18, the patient presented sexual infantilism, a micropenis and gynecomastia. No mutation was revealed in GnRHR, TACR3/TAC3, PROK2/PROKR2 and PROP1 genes, except a homozygous intronic variation (c.244 + 128C>T; dbSNP: rs350129) in the KISS1R gene, which is likely nondeleterious. A homozygous splice-donor site mutation (IVS14 + 1G>A) was found in the AAAS gene. This mutation, responsible for AAAS, is a founder mutation in North Africa. Conclusion: This is the first report on a Tunisian patient with the coexistence of AAAS and CHH. The diagnosis of CHH should be taken in consideration in patients with Allgrove syndrome and who carry the IVS14 + 1G>A mutation as this might challenge appropriate genetic counseling.

Comorbidity in the Tunisian population

“…Founder mutations are responsible for distal renal tubular acidosis and maple syrup urine disease in families from two localities originating from Central Tunisia in whom familial comorbidities were frequently reported (unpublished). Moreover, the individual comorbidity of Allgrove syndrome and congenital hypogonadotropic hypogonadism of the patient reported by Cherif Ben Abdallah et al is likely due to past isolation and subsequent consanguinity . In fact, the patient family descends from common ancestors going back to around six and seven generations and originating from the island of Jerba .…”

“…Moreover, the individual comorbidity of Allgrove syndrome and congenital hypogonadotropic hypogonadism of the patient reported by Cherif Ben Abdallah et al is likely due to past isolation and subsequent consanguinity . In fact, the patient family descends from common ancestors going back to around six and seven generations and originating from the island of Jerba .…”

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome

“…The Co-occurence of two or several diseases has been recently reported in Tunisian population. This phenomenon has been observed mainly for autosomal recessive diseases and is due to the high rate of consanguinity [ 45 , 46 ]. Nevertheless, the association we report between NS and IP is probably coincidental since no link has been established among the 2 pathophysiological pathways and high rates of consanguinity in the Tunisian patients’ population are not likely to influence the appearance of IP nor NS, whose inheritance patterns are not autosomal recessive.…”

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

“…While the exact function of the ALADIN protein remains mostly unclear, attempts have been made to clarify the pathogenetic mechanism of the different mutations reported, seemingly causing impaired nuclear import of DNA repair proteins and the intensification of oxidative stress status in the cell. Figure 1) 3,9,41,[61][62][63][64][65][66][67][68][69]10,[70][71][72][73][74][75][76][77][78][79]11,[80][81][82][83][84][85][86][87][88][89]12,[90][91][92][93][94][95][96][97][98][99]16,[100][101]<...>…”