Familial acromegaly with a novel PRKAR1A splice-acceptor variant and marked intrafamilial phenotypic variability

Abstract

Acromegaly is usually sporadic but may rarely occur as part of inherited endocrine tumor syndromes, particularly when disease onset is early or multiple family members are affected. Carney complex is an autosomal dominant disorder, most often due to inactivating PRKAR1A mutations, with diverse endocrine and nonendocrine manifestations. We report a 33-year-old man with long-standing acromegaly, growth hormone (GH)-positive pituitary adenoma with focal prolactin positivity, cutaneous and cardiac myxomas, and bilateral large-cell calcifying Sertoli cell tumors. He achieved biochemical remission after endoscopic transsphenoidal surgery. His younger sister had childhood-onset acromegaly requiring pituitary surgery in adolescence and has persistent disease with mildly elevated insulin-like growth factor-1 (IGF-1). She subsequently had a spontaneous pregnancy and delivered a healthy child. Genetic analysis of the index case, sister, and mother identified a novel monoallelic intronic PRKAR1A splice-acceptor variant, c.709-7T>G, in intron 7 near exon 8, causes retention of 6 base pairs from the 3′ end of intron 7, leading to a frameshift and premature truncation, p. (Gly237insPhefs*2), consistent with a likely pathogenic variant. The mother did not develop any endocrine manifestations till date (62 years of age). This report expands the PRKAR1A mutational spectrum and highlights marked intrafamilial phenotypic variability, supporting genetic evaluation in early-onset or familial acromegaly to guide surveillance and family screening.

Introduction

Acromegaly is a rare endocrine disorder caused by chronic excess secretion of growth hormone (GH), most commonly due to a pituitary adenoma, leading to elevated circulating insulin-like growth factor-1 (IGF-1) levels [1]. The disease presents with characteristic clinical features, multisystem complications, and increased morbidity and mortality if diagnosis and treatment are delayed. While most acromegaly cases are sporadic, a small proportion—particularly early-onset cases—occur in familial settings, often as part of genetic syndromes such as familial isolated pituitary adenoma, multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), and Carney complex [1, 2].

Carney complex is a rare autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, myxomas, endocrine hyperfunction, and schwannomas [3]. Endocrine manifestations frequently include pituitary adenomas, primary pigmented nodular adrenocortical disease, and large-cell calcifying Sertoli cell tumors (LCCSCTs) of the testes [3, 4]. Germline variants in the PRKAR1A gene—coding for the regulatory subunit of the protein kinase A—are the primary cause of Carney complex [4, 5]. Loss-of-function PRKAR1A variants—including nonsense, frameshift, splice-site mutations causing premature termination and nonsense-mediated decay, as well as large genomic deletions—lead to constitutive activation of cAMP-dependent protein kinase A signaling, promoting endocrine tumorigenesis [4-6]. Pituitary involvement in Carney complex is variable and often under-recognized, with GH excess sometimes preceding the diagnosis by several years [6, 7].

Pituitary adenomas associated with Carney complex are frequently plurihormonal and may demonstrate aggressive or persistent disease despite surgical intervention [7]. Skin lesions and extracutaneous findings such as LCCSCTs are important diagnostic clues and should prompt evaluation for a syndromic cause, especially in early-onset or familial acromegaly [2, 7].

We report familial acromegaly due to a novel monoallelic PRKAR1A splice-acceptor variant. The index patient had acromegaly, cutaneous and cardiac myxomas, and large-cell calcifying Sertoli cell tumors. His sister had childhood-onset acromegaly with persistent biochemical disease, while their carrier mother showed no overt endocrine manifestations and only limited cutaneous findings in the form of few lentigines in the malar region of the face. This family highlights marked intrafamilial variability and reduced endocrine penetrance in PRKAR1A-related disease, underscoring the need for phenotypic evaluation, family screening, and genetic testing in early-onset or familial acromegaly.

Case presentation

The index patient was a 33-year-old man, born of a nonconsanguineous marriage, presented with long-standing features of GH excess evolving over 10 years. He first noticed voice deepening at 23 years, followed by progressive enlargement of the hands and feet by 26 years and multiple painless truncal cutaneous nodules over the preceding 3 years. At 30 years, he developed decreased libido, erectile dysfunction, and infertility. He had no symptoms suggestive of mass effect, hypercortisolism, thyroid dysfunction, nephrolithiasis, fractures, polyuria, or polydipsia. Past history was unremarkable, with no prior radiation exposure, head trauma, chronic illness, cardiac disease, arrhythmia, embolic events, or family history of sudden cardiac death. On examination, he was hemodynamically stable with coarse facial features, prognathism, and acral enlargement (Fig. 1). Height was 184 cm with an arm span of 188 cm. Multiple small, painless subcutaneous trunk nodules were present clinically (Fig. 2A-2D) and were histologically confirmed as cutaneous angiomyxomas (Fig. 2E and 2F). Biopsy of an eyelid lesion confirmed the presence of a schwannoma. There were no lentigines, blue nevi, café-au-lait macules, or mucocutaneous pigmentation. Thyroid, visual field, cardiovascular, and neurological examinations were normal. Genital examination revealed bilaterally enlarged, firm, nodular testes without gynecomastia, with age-appropriate secondary sexual characteristics.

Figure 1.

Clinical features of acromegaly in the index patient. (A) Facial photograph showing coarse features and prognathism. (B) Photograph of the hands showing acral enlargement, consistent with long-standing growth hormone excess.

Figure 2.

Cutaneous and testicular manifestations of carney complex in the index patient. (A-D) Photographs showing multiple soft, painless papulonodular lesions involving the periorbital region, trunk, and groin, consistent with cutaneous myxomas, a characteristic cutaneous manifestation of Carney complex. A small nodular lesion in the right lower eyelid was a biopsy-proven schwannoma. (E-F) Skin biopsy showing flattened epidermis with deposition of pale mucinous material within the dermis (hematoxylin and eosin stain, ×200). Dermal mucin is highlighted by Alcian blue staining (×200). (G-H) Scrotal ultrasonography demonstrating bilateral intratesticular, well-defined hyperechoic lesions with calcifications, characteristic of large-cell calcifying Sertoli cell tumors.

Diagnostic assessment

Biochemical evaluation of the index case confirmed active acromegaly which is depicted in (Table 1).

Table 1.

Baseline biochemical and hormonal evaluation of the index patient

Parameter	Value (SI units)	Value (Conventional units)	Reference range (SI and conventional)
Hemoglobin	128 g/L	12.8 g/dL	130-170 g/L (13.0-17.0 g/dL)
Serum calcium	2.45 mmol/L	9.8 mg/dL	2.15-2.55 mmol/L (8.6-10.2 mg/dL)
Alkaline phosphatase	80 U/L	80 U/L	42-128 U/L
AST	33 U/L	33 U/L	2-40 U/L
ALT	26 U/L	26 U/L	2-41 U/L
HbA1c	42 mmol/mol	6.0%	18-41 mmol/mol (3.8-5.9%)
Growth hormone (GH)	13.1 µg/L	13.1 ng/mL	0.0-2.5 µg/L (0.0-2.5 ng/mL)
IGF-1	139.9 nmol/L	1069 ng/mL	15-32 nmol/L (114-247 ng/mL)
Nadir GH during oral glucose tolerance test	12.3 µg/L	12.3 ng/mL	<0.4 µg/L (<0.4 ng/mL)
Free T4	10.0 pmol/L	0.78 ng/dL	11.6-29.6 pmol/L (0.9-2.3 ng/dL)
TSH	1.87 mIU/L	1.87 µIU/mL	0.27-4.2 mIU/L (0.27-4.2 µIU/mL)
LH	1.40 IU/L	1.40 IU/L	1.7-8.6 IU/L
FSH	2.34 IU/L	2.34 IU/L	1.5-12.4 IU/L
Morning cortisol	250 nmol/L	9.1 µg/dL	171-536 nmol/L (6.2-19.4 µg/dL)
ACTH	5.5 pmol/L	25 pg/mL	1.6-13.9 pmol/L (7.2-63.3 pg/mL)
Total testosterone	4.6 nmol/L	132 ng/dL	8.3-33.0 nmol/L (240-950 ng/dL)
Prolactin	1700 mIU/L	80 ng/mL	85-320 mIU/L (4-15 ng/mL)

Abbreviations: ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating hormone; GH, growth hormone; HbA1c, glycated hemoglobin; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; T4, thyroxine; TSH, thyroid-stimulating hormone.

Scrotal ultrasonography showed bilateral well-defined hyperechoic intratesticular lesions with calcifications, suggestive of LCCSCTs (Fig. 2G and 2H), without features of malignancy or lymphadenopathy. His pituitary magnetic resonance imaging (MRI) revealed a well-circumscribed sellar lesion measuring 11.8 × 11.2 × 8.7 mm, confined to the sella, with Knosp grade 0, intact sellar floor, and no suprasellar extension or optic chiasmal compression (Fig. 3A-3C). Echocardiography followed by cardiac MRI revealed a small well-defined intracardiac lesion at the left atrioventricular junction, consistent with cardiac myxoma. Thyroid ultrasonography was normal.

Figure 3.

Pituitary imaging and histopathology of the adenoma of the index patient. (A-C) Contrast-enhanced magnetic resonance imaging of the pituitary demonstrates a well-circumscribed sellar lesion measuring 11.8 × 11.2 × 8.7 mm, confined to the sella, with Knosp grade 0, intact sellar floor, and no suprasellar extension or optic chiasmal compression. (D) Hematoxylin and eosin staining demonstrates features of a sparsely granulated pituitary adenoma (×200). (E-F) Immunohistochemistry shows growth hormone and prolactin positivity in approximately 30% to 40% of tumor cells (×200), consistent with a plurihormonal PIT-1 lineage adenoma with somatotroph and lactotroph differentiation. (G) Somatostatin receptor subtype (SSTR) 2 immunohistochemistry showing weak and variable staining in tumor cells compared with normal entrapped pituicytes (black arrow) (×200). (H) SSTR5 immunohistochemistry showing strong cytoplasmic expression in tumor cells (×200).

Treatment

The index patient underwent endoscopic transsphenoidal surgery. Histology showed a sparsely granulated pituitary adenoma, with GH and prolactin positivity in 30% to 40% of tumor cells, consistent with a plurihormonal PIT-1 lineage adenoma with somatotroph and lactotroph differentiation (Fig. 3D-3F). Somatostatin receptor (SSTR) immunohistochemistry showed weak, variable SSTR2 staining and strong cytoplasmic SSTR5 expression in tumor cells (Fig. 3G and 3H). Ki-67 was low (<3%), mitoses were infrequent (<1/10 HPF), and there was no atypia. Testicular biopsy demonstrated features consistent with LCCSCT, supporting an underlying Carney complex spectrum disorder.

The Index patient's younger sister had childhood-onset GH excess and underwent transsphenoidal surgery at 16 years of age. She has persistent biochemical disease, with elevated GH and IGF-1 levels (1.2 × upper limit of normal), and is currently not receiving any therapy due to personal choice. Her other hormonal axes are normal. The current clinical appearance of the sister of index case is shown in (Fig. 4A-4C), and her repeat pituitary MRI demonstrates a residual sellar lesion measuring 6.8 × 5.7 × 9.7 mm, consistent with persistent disease (Fig. 4D and 4E). She continues to have persistent acromegaly at 7 years of follow up. She had a spontaneous pregnancy, delivering a healthy female infant weighing 3 kg, who is currently 2.5 years old with normal growth and development. Genetic counseling and testing have been recommended for the child. Detailed clinical, dermatologic, hormonal, and biochemical evaluation of the mother showed no overt features of Carney complex, with no evident features of GH excess, cutaneous myxomas, or characteristic mucosal pigmentation but there were lentigines on the face (Fig. 4F and 4G).

Figure 4.

Clinical appearance and pituitary imaging of the affected sister and mother. (A-C) Clinical photographs of the younger sister showing features consistent with acral enlargement and tall stature. (D) Recent pituitary MRI (coronal T1 postcontrast and (E) T2 noncontrast) images of the younger sister showing a residual sellar lesion measuring 6.8 × 5.7 × 9.7 mm, consistent with persistent disease after prior transsphenoidal surgery. (F-G) Photographs of the mother showing no evident features of growth hormone excess, cutaneous myxomas, or characteristic mucocutaneous pigmentation, except few lentigines in the malar area of the face.

Outcome and follow-up

After pituitary surgery, biochemical remission was achieved without medical therapy or radiotherapy. The LCCSCTs were managed conservatively because of their benign appearance, absence of estrogen excess, and lack of malignant features, with planned clinical and ultrasonographic surveillance. The small asymptomatic cardiac myxoma was also observed with periodic echocardiography; at 3-year follow-up, it had regressed on cardiac MRI, although new cutaneous myxomas had appeared. Postoperative evaluation confirmed remission of the GH excess, with a nadir GH of 0.356 ng/mL (SI: 0.356 µg/L) and normalized IGF-1. The patient reported improvement in acral symptoms and sexual function. Postoperatively, hypogonadotropic hypogonadism persisted, with luteinizing hormone 1.2 IU/L, follicle-stimulating hormone (FSH) 2.0 IU/L, and total testosterone 145 ng/dL (SI: 5.0 nmol/L). He is currently on levothyroxine and alternate-day subcutaneous FSH for spermatogenesis. Semen analysis showed a sperm concentration of 35 million/mL with predominant necrozoospermia, 7% normal morphology, and markedly reduced progressive motility. Follow-up pituitary MRI showed no residual or recurrent adenoma. Persistent hypogonadotropic hypogonadism with abnormal semen parameters warrants ongoing gonadotropin therapy and fertility counseling in form of assisted reproduction with preimplantation genetic testing for Carney complex and selective implantation of unaffected embryos was advised. He remains under surveillance with annual IGF-1, periodic pituitary MRI, testicular monitoring, and screening for other Carney complex manifestations, including cardiac and thyroid evaluation.

In view of childhood-onset disease in the sibling, familial clustering, and the presence of extracutaneous manifestations (LCCSCTs), genetic testing was pursued. Sequencing identified a novel monoallelic intronic PRKAR1A splice-acceptor region variant, c.709-7T>G, located in intron 7 near the splice acceptor site of exon 8. Functional analysis demonstrated retention of 6 intronic nucleotides (TTTTAG) at the exon 7 to 8 junction, resulting in a frameshift mutation (p.Gly237insPhefs*2) and a predicted premature termination codon, consistent with loss of PRKAR1A function likely via nonsense-mediated mRNA decay (Fig. 5A and 5B). The c.709-7T>G substitution changes the local sequence from ttttTG to ttttAG, thereby creating a novel canonical splice acceptor site. This variant was classified as pathogenic according to American College of Medical Genetics and Genomics criteria, establishing the diagnosis of familial acromegaly within the Carney complex spectrum.

Figure 5.

Genetic analysis of the index patient. Top panel: Schematic representation of the monoallelic PRKAR1A c.709-7T>G; p.(Gly237insPhefs*2) variant located in intron 7 near the splice acceptor site of exon 8. The c.709-7T>G substitution changes the sequence from ttttTG to ttttAG, creating a novel canonical splice acceptor site and resulting in retention of 6 intronic nucleotides marked in green. (A) Bottom panel: Sanger sequencing of reverse transcription polymerase chain reaction products derived from patient RNA demonstrating aberrant splicing associated with the PRKAR1A c.709-7T>G variant, resulting in retention of 6 base pairs (TTTTAG) at the intron 7 and exon 8 boundary, same depicted in electropherogram (B).

Genetic testing in the affected sister confirmed the same monoallelic PRKAR1A variant, supporting disease segregation. The mother was also heterozygous for the variant, while her other siblings tested negative (Fig. 6).

Figure 6.

Three-generation pedigree showing segregation of the monoallelic PRKAR1A c.709-7T>G variant. Squares indicate males and circles indicate females. Solid-filled symbols indicate gigantism, and shaded symbols indicate acromegaly. A central dot indicates carriers of the PRKAR1A variant. Unfilled symbols indicate apparently unaffected family members without the PRKAR1A variant on available testing. A diagonal slash denotes deceased individuals, and the arrow indicates the proband. The pedigree supports autosomal dominant inheritance with variable expressivity and reduced penetrance, particularly in the carrier mother.

Discussion

The individuals reported in this study illustrate marked intrafamilial variability of PRKAR1A-related disease and highlight several clinically important aspects of Carney complex-associated acromegaly. Although the index patient presented in adulthood with multisystem Carney complex manifestations, his sister developed GH excess during childhood, whereas their carrier mother had no overt endocrine manifestations and only limited or absent cutaneous expression. This pattern supports marked variable expressivity among affected family members and reduced penetrance for endocrine manifestations in the mother [8].

Pituitary adenomas associated with PRKAR1A mutations differ from sporadic tumors in several respects. They are frequently plurihormonal, may arise on a background of diffuse pituitary hyperplasia, and can show variable surgical outcomes, including persistence or recurrence after transsphenoidal surgery [9]. This was evident in the individuals reported in this study, where the index patient achieved biochemical remission following surgery, whereas his sister had persistent disease without any medical therapy. We advised the affected sister to initiate somatostatin receptor ligand therapy; however, she declined. Data on the efficacy of somatostatin receptor ligands in Carney complex–associated acromegaly are limited, with only isolated case reports demonstrating variable response, including resistance or partial biochemical control [10, 11] These observations underscore the need for individualized management and long-term surveillance in genetically predisposed patients.

The presence of LCCSCTs in the index patient was a key diagnostic clue. Typically, bilateral and benign, these tumors are characteristic of Carney complex and should prompt evaluation for associated endocrine neoplasms, particularly pituitary adenomas [8, 12]. In men with acromegaly, the presence of LCCSCTs strongly suggests a syndromic etiology and should prompt early genetic testing.

In the index patient, immunohistochemistry showed weak, variable SSTR2 staining and strong cytoplasmic SSTR5 expression. This pattern may be relevant for selecting somatostatin receptor ligand therapy, although treatment-response correlation could not be assessed as he achieved postoperative biochemical remission without medical therapy.

The identification of a novel intronic splice-site mutation in the PRKAR1A gene (c.709-7T>G) expands the mutational spectrum. Splice-acceptor region variants leading to intron retention and frameshift mutations are a recognized mechanism of PRKAR1A inactivation, resulting in haploinsufficiency due to nonsense-mediated mRNA decay [10]. The variant lies in intron 7 near the splice acceptor site of exon 8 and functionally creates a novel canonical splice acceptor sequence, changing ttttTG to ttttAT. Pathogenicity is supported by multisystem involvement and familial clustering. Mere presence lentigines without classical manifestations like cardiac myxoma, Pituitary neuroendocrine tumor or primary pigmented micronodular adrenal disease does not exclude the diagnosis as penetrance may be incomplete and expressivity variable and time-dependent. Inefficient alternative splicing may explain milder expression in the asymptomatic carrier mother [13]. Penetrance of Carney complex in PRKAR1A variant carriers exceeds 95% by age 50. Only 2 variants—c.709-7_709-2delTTTTTA and c.1A>G (p.Met1Val)—are linked to incomplete penetrance, usually with a milder phenotype, most often primary pigmented nodular adrenocortical disease with or without lentigines [14]. The carrier mother's lack of endocrine disease, with only limited cutaneous findings, suggests reduced penetrance for endocrine manifestations rather than complete absence of disease expression. By contrast, the differing onset, severity, and associated features in the index patient and his sister reflect variable expressivity among affected carriers.

This case emphasizes the need to suspect a genetic cause in early-onset or familial acromegaly, especially when associated with plurihormonal adenomas or extracutaneous tumors. Genetic confirmation allows focused surveillance and family screening, while the wide variation within this family suggests variable expressivity and reduced penetrance of PRKAR1A-related disease.

Learning points

• Early-onset or familial acromegaly, particularly when associated with extracutaneous tumors such as large-cell calcifying Sertoli cell tumors, should prompt evaluation for PRKAR1A-related Carney complex.

• PRKAR1A splice-acceptor variants may show marked intrafamilial variable expressivity, and mildly affected or apparently asymptomatic carriers still require long-term surveillance.

• Establishing a molecular diagnosis enables surveillance for associated neoplasms, reproductive counseling, and cascade screening of at-risk relatives.

Contributors

V.J. and P.D. were involved in patient management and conceptualized the report. V.J. collected clinical data and drafted the manuscript. S.B. performed and interpreted the genetic analysis. D.C. performed histopathological evaluation and interpretation. V.K. collected the patient data, performed the immunohistochemistry, and contributed to subsequent revisions of the manuscript. M.K. conceptualized, supervised the genetic analysis and critically revised the manuscript. P.D. made the diagnosis, supervised the study and critically revised the manuscript. All authors reviewed and approved the final manuscript.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed patient consent for publication

Signed informed consent obtained directly from patient, his affected sister, and the mother.

Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. The PRKAR1A variant data have been submitted to ClinVar, and the accession number is pending. Additional anonymized clinical data are available from the corresponding author on reasonable request.