Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder
Abstract
:1. Introduction
2. Isolated Acromegaly
2.1. Familial Isolated Pituitary Adenomas—FIPAs
2.1.1. Aryl Hydrocarbon Receptor-Interacting Protein (AIP)
2.1.2. G Protein-Coupled Receptor 101 (GPR101)–X-Linked Acrogigantism (X-LAG)
2.1.3. Unknown Mutations
2.2. Sporadic Acromegaly
2.2.1. AIP
2.2.2. GNAS Complex Locus (GNAS)
2.2.3. Higher Gastric Inhibitory Polypeptide Receptor (GIPR) Expression
3. Syndromic Acromegaly
3.1. Multiple Endocrine Neoplasia Type 1 (MEN1)
3.2. Multiple Endocrine Neoplasia Type 4 (MEN4)
3.3. Carney Complex (CNC)
3.4. McCune–Albright Syndrome (MAS)
3.5. 3P Association (3Pa)
3.6. Neurofibromatosis Type 1 (NF1)
3.7. Tuberous Sclerosis Complex (TSC)
3.8. Multiple Endocrine Neoplasia Type 2 (MEN2)
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Type | Disease/Syndrome | Gene(s) | Location | Inheritance | Penetrance | Prevalence of Acromegaly | Clinical Particularities | Histological Particularities | Treatment Particularities | References |
---|---|---|---|---|---|---|---|---|---|---|
Isolated | FIPAs | AIP (germline) | 11q13.2 | AD | 20–33% | 10–15% of FIPA families | Male predominance; age at diagnosis: median 23 years, mean 23.6 ± 11.2 years | Usually macroadenomas, sparsely granulated, low SSR2 expression | Resistance to I gen SAs; need for radiotherapy, repeated surgery, and multimodal therapy more often | [11,14,15,16,17,18,19,20,21,22,23] |
GPR101 (germline + somatic) | Xq26.3 | X-linked | 100%, but 72.2% are de novo mutations | 7.8% of FIPAs | Female predominance; earlier age at diagnosis (median, 3.4–4.4 years; mean, 4.7 years) | 75% macroadenomas; 25% pituitary hyperplasia; generally, SSR2 is present, but SSR5 is variably present | SAs show poor results, Pegvisomant is more effective | [24,25,26,27] | ||
CDH23 | 10q22.1 | ? | ? | Proposed as FIPA members, possible generators of GH-secreting PitNETs | ? | ? | ? | [22,28,29,30] | ||
IGSF1 | Xq26.1 | |||||||||
PAM | 5q21.1 | |||||||||
Sporadic defects in genes involved in other diseases/syndromes | AIP (germline) | 11q13.2 | ? | ? | 3.4–5% of AIP-positive cases | Male predominance; age at diagnosis: mean, 23.5 ± 4.2 years | Usually macroadenomas, sparsely granulated, low SSR2 expression | 8% of SA-resistant cases | [14,19,31,32,33] | |
GNAS (somatic) | 20q13.32 | ? | ? | 30–40% of GH-secreting PitNETs | Older patients (age at diagnosis: mean, 42.0 ± 1.6 years; median, 41 years), higher IGF-1 | Smaller, less invasive tumors; usually densely granulated; higher levels of DRD2 | Improved responses to surgery and to I gen SAs | [34,35,36,37,38,39,40,41,42,43] | ||
Sporadic higher GIPR expression | GIPR | 19q13.32 | ? | ? | 24–27.4% of acromegaly | Paradoxical increase in GH levels following OGTT; higher IGF-1; mean age at diagnosis: 44.08 ± 12.37 years | Smaller densely granulated adenomas; ectopic expression of GIP receptor in somatotropinomas | Good response to SAs | [22,44,45,46] | |
Syndromic | MEN1 | MEN1 (mostly germline, but somatic variants exist too) | 11q13.1 | AD | 100% | 2.9–18.5% of acromegaly | Slight female predominance (59.1%); older age (mean 54.2 ± 15.9 years) | 65–85% macroadenomas | Poor response to drug therapy but better prognosis compared to AIP-positive adenomas | [10,47,48,49,50,51,52,53,54,55,56,57] |
MEN2 | RET (germline, but in some cancers can be somatic) | 10q11.21 | AD | 100% | Three cases of RET mutations reported | 44 (48-year-old female; 35-year-old male) | Prolactin co-secretion in two cases (data available only for two cases) | ? | [22,58,59,60,61] | |
MEN4 | CDKN1B (germline) | 12p13.1 | AD | Most probably 100% | 7–10% of MEN4 | Similar to MEN1 but milder symptoms and undetermined mean age | ? | Standard therapy | [3,22,40,62,63,64,65] | |
Carney complex type 1 | PRKAR1A | 17q24.2 | 70% AD, 30% de novo | >95% | 10% of the CNC | Feminine prevalence. Age at diagnosis: median, 25.3–28.8 years; mean, 31 years | 70% pituitary hyperplasia ± adenomas; same proportion of micro- and macroadenomas | Probably normal response: a small proportion of subjects are considered resistant to treatment | [10,22,54,66,67,68,69,70,71,72] | |
PDE11A | 2q31.2 | |||||||||
PRKACB | 1p31.1 | |||||||||
PRKACA | 19p13.12 | |||||||||
(germline) | ||||||||||
McCune–Albright syndrome | GNAS (somatic–mosaic) | 20q13.32 | Not inherited | - | 20–30% of MAS | Male prevalence: mean age at diagnosis is 24.4 years | Only 54% of the patients have an adenoma | Poor response to surgery alone; 70% are not fully controlled under I gen SAs; Pegvisomant and Pasireotide have good response | [73,74,75,76] | |
3P association | MAX | 14q23.3 | AD | ? | Extremely rare | Higher age of onset than AIP/MEN1: mean, 42.4 years | Aggressive macroadenomas, intracytoplasmic vacuoles | Patients with MAX mutations require a multimodal treatment approach | [3,10,77,78,79] | |
SDHA | 5p15.33 | |||||||||
SDHAF2 | 11q12.2 | |||||||||
SDHB | 1p36.13 | |||||||||
SDHC | 1q23.3 | |||||||||
SDHD | 11q23.1 | |||||||||
TMEM127 | 2q11.2 | |||||||||
(germline) | ||||||||||
Neurofibromatosis type 1 | NF1 (germline, but in some cancers can be somatic) | 17q11.2 | AD | 100% | 10% of NF1 | Mainly seen in children but can also appear in adolescents and adults; mean age at diagnosis: 4.5 years | Most are pituitary adenomas, some are pituitary hyperplasia, and some have no pituitary anomalies at all; a significant proportion of patients also have OPG | In NF1 children with OPG, GH excess can be reversed, and short-term SA therapy could be sufficient | [10,80,81,82,83,84,85,86] | |
Tuberous sclerosis complex | TSC1 | 9q34.13 | AD, though expressivity is variable | 100% | Only two cases reported | Age at diagnosis: 9 years old (available for just one case) | Macroadenoma (available for just one case); Prolactin co-secretion (two cases) | ? | [22,87,88,89] | |
TSC2 | 16p13.3 | |||||||||
(germline) |
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Balinisteanu, I.; Caba, L.; Florea, A.; Popescu, R.; Florea, L.; Ungureanu, M.-C.; Leustean, L.; Gorduza, E.V.; Preda, C. Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder. Curr. Issues Mol. Biol. 2024, 46, 9093-9121. https://doi.org/10.3390/cimb46080538
Balinisteanu I, Caba L, Florea A, Popescu R, Florea L, Ungureanu M-C, Leustean L, Gorduza EV, Preda C. Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder. Current Issues in Molecular Biology. 2024; 46(8):9093-9121. https://doi.org/10.3390/cimb46080538
Chicago/Turabian StyleBalinisteanu, Ioana, Lavinia Caba, Andreea Florea, Roxana Popescu, Laura Florea, Maria-Christina Ungureanu, Letitia Leustean, Eusebiu Vlad Gorduza, and Cristina Preda. 2024. "Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder" Current Issues in Molecular Biology 46, no. 8: 9093-9121. https://doi.org/10.3390/cimb46080538