Monoallelic PARN mutation presenting as pancytopenia, hepatic fibrosis and idiopathic pulmonary fibrosis

Summary

A woman in her late 20s presented with a 5-year history of progressive fatigue and generalised weakness. Examination revealed signs of premature ageing, anaemia, neuropathy and hepatosplenomegaly.

Investigations showed pancytopenia, dimorphic anaemia, severe vitamin B₁₂ deficiency, hepatic fibrosis and pulmonary fibrosis. Despite correction of nutritional deficiencies, the constellation of cytopenia, premature greying, osteoporosis, hepatic and pulmonary fibrosis raised suspicion of a genetic disorder. Clinical exome sequencing identified a monoallelic PARN missense variant (c.613T>C; p.Cys205Arg), classified as a Variant of Uncertain Significance. Germline pathogenic variants in PARN have been associated with dyskeratosis congenita, autosomal recessive 6 (DKCB6) and with telomere-related pulmonary fibrosis and/or bone marrow failure 4. The clinical–genetic correlation in this case supported a diagnosis of a telomere biology disorder (TBD). This case highlights the importance of considering TBDs in young adults with unexplained multisystem disease, even when classical mucocutaneous features are absent. Early recognition is crucial for guiding genetic counselling, surveillance and consideration of bone marrow transplantation in progressive cases.

Background

Telomere biology disorders (TBDs) are rare premature-ageing syndromes caused by Mendelian defects in telomere-related genes that lead to abnormally short or dysfunctional telomeres.¹ Actively dividing cells, such as bone marrow, skin, mucosa, hair and hepatocytes, are predominantly affected cell groups. TBD includes numerous clinical phenotypes, with dyskeratosis congenita (DC) being the prototype disease. Other entities include Hoyeraal-Hreidarsson (HH) syndrome, Revesz syndrome and Coats plus syndrome.²

Among the various mutations identified in this group of disorders, PARN variants demonstrate a distinct phenotype, with biallelic variants causing autosomal recessive dyskeratosis congenita (DKCB6), while monoallelic variants more often underlie telomere-related pulmonary fibrosis and/or bone marrow failure (PFBMFT4).^{3 4}

We describe a woman in her late 20s with prolonged fatigue and multisystem involvement who was ultimately diagnosed with a TBD.

Case presentation

A woman in her late 20s presented to our tertiary care centre with a 5-year history of progressively worsening generalised weakness and early fatigability. Over the years, her functional capacity declined, reducing her ability to perform daily activities compared with her peers. In the last 3 months, the weakness has worsened to the point of impairing self-care and requiring assistance. She also reported exertional dyspnoea, intermittent chest discomfort, weight loss and anorexia.

On examination, she was haemodynamically stable. Notable findings included pallor, icterus, premature greying of hair, knuckle hyperpigmentation and a bald tongue with atrophy of lingual papillae.

Musculoskeletal examination revealed thoracic scoliosis and bilateral thenar atrophy. Abdominal examination showed hepatomegaly (5 cm below the right costal margin, span 18 cm). Respiratory examination revealed reduced breath sounds in the bilateral infra-scapular regions. Cardiovascular examination was unremarkable.

Investigations

Initial laboratory evaluation showed pancytopenia with a low reticulocyte count (0.39%). Peripheral smear demonstrated dimorphic erythrocytes, basophilic stippling, Cabot rings and hypersegmented neutrophils—suggestive of ineffective erythropoiesis. Serum studies confirmed severe vitamin B₁₂ and folate deficiency. Iron studies revealed elevated serum iron and ferritin, consistent with ineffective erythropoiesis (table 1).

Table 1. Laboratory investigations for evaluation of cytopenia.

Parameter	Value	Normal range
Haemoglobin	30g/L	120–155 g/L
Total leucocyte count	3.3 ×10 9 /L	4–11×10 9 /L
Platelet count	33×10³/μL	150–450×10³/μL
Immature platelet fraction	18.9%	1%–7%
Reticulocyte count	0.39%	0.5%–2.5%
Serum vitamin B12	<83 pg/mL	200–900 pg/mL
Serum folate	2.8 ng/mL	3–17 ng/mL
Serum iron	151 µg/dL	60–170 µg/dL
Serum ferritin	3553 ng/mL	15–200 ng/mL
Haemoglobin-F	3%	<1%
Haemoglobin-A2	4.2%	1.5%–3.5%
Lactate dehydrogenase	1347 IU/L	140–280 IU/L

Bone marrow examination revealed trilineage haematopoiesis with erythroid hyperplasia and increased iron stores, without evidence of malignancy, dysplasia or infiltrative disease; cytogenetic analysis was also normal.

Markers of haemolysis included elevated lactate dehydrogenase and indirect hyperbilirubinaemia. The direct antiglobulin test (DAT) was positive for IgG (2+), while the indirect test was negative. Despite this, the low reticulocyte response and marrow findings were more consistent with ineffective erythropoiesis rather than peripheral immune-mediated destruction.

To evaluate gastrointestinal malabsorption, an upper gastrointestinal endoscopy was performed, which appeared macroscopically normal. Duodenal biopsy showed mild chronic gastritis with reduced parietal cells, possibly contributing to B₁₂ malabsorption via impaired intrinsic factor production. However, the severity of clinical findings appeared disproportionate to nutritional deficiency alone.

Hepatic dysfunction prompted further imaging and assessment. Abdominal ultrasound revealed hepatosplenomegaly. Transient elastography showed grade II hepatic steatosis (controlled attenuation parameter: 295 dB/m) and cirrhosis (liver stiffness: 18.1 kPa). Inflammatory markers were raised. However, autoimmune serologies, including antinuclear and autoimmune hepatitis antibodies, were negative. Infectious workup for viral hepatitis, HIV, Cytomegalovirus and scrub typhus was largely unremarkable except for positive Epstein-Barr virus IgG (table 2).

Table 2. Laboratory investigations related to liver function and systemic inflammation.

Parameter	Value	Normal range
Total bilirubin	4.96 mg/dL	0.3–1.2 mg/dL
Direct bilirubin	2.56 mg/dL	0.1–0.4 mg/dL
Aspartate aminotransferase	262 IU/L	10–40 IU/L
Alanine aminotransferase	95 IU/L	10–40 IU/L
Gamma-glutamyl transferase	281 IU/L	9–36 IU/L
Serum albumin	2.68 g/dL	3.5–5.0 g/dL
Prothrombin time	20.8 s	11–13.5 s
INR (International Normalized Ratio)	1.7	0.8–1.2
Activated partial thromboplastin time	52 s	L25–35 s
Fibrinogen equivalent units	1.72 mcg/dL	<0.5 mcg/dL
Serum IgG	2291 mg/dL	700–1600 mg/dL
C reactive protein	24.7 mg/L	<6 mg/L
Erythrocyte sedimentation rate	115 (corrected 62.5) mm/hour	<20 mm/hour
Procalcitonin	<0.05	<0.05 ng/mL

To evaluate occult infiltrative or inflammatory pathology, positron emission tomography–CT was performed. It showed inhomogeneous ¹⁸F-fluorodeoxyglucose uptake in the axial and appendicular bone marrow. Diffuse ground-glass haziness with multiple fibrotic and subpleural atelectatic changes was noted in both lung fields, along with hepatosplenomegaly and ascites, but without evidence of overt malignancy or granulomatous disease (figures1 2).

Figure 1. Positron emission tomography–CT showing inhomogeneous ¹⁸F-fluorodeoxyglucose uptake in the axial and appendicular bone marrow along with hepatosplenomegaly and ascites. 3D, 3 -dimensional; WBCE, Whole body contrast-enhanced.

Figure 2. CT showing diffuse ground-glass haziness with multiple fibrotic (arrow) and subpleural atelectatic changes was noted in both lung fields.

Additional findings included secondary hyperparathyroidism, electrolyte disturbances (hypocalcaemia, hypokalaemia), vitamin D deficiency and osteoporosis confirmed on dual-energy X-ray absorptiometry, explaining her recurrent bone pain and fractures (table 3). Electromyography and nerve conduction studies revealed asymmetric sensorimotor axonal polyneuropathy with chronic neurogenic changes in proximal and distal muscle groups.

Table 3. Laboratory investigations related to mineral, metabolic and trace element assessment.

Parameter	Value	Normal range
Triglycerides	165 mg/dL	<150 mg/dL
Serum lead	Normal	<10 µg/dL
Ceruloplasmin	Normal	20–60 mg/dL
Parathyroid hormone	660 pg/mL	10–65 pg/mL
Serum calcium	5.78 (corrected 6.8) mg/dL	8.5–10.5 mg/dL
Serum potassium	2.87 mEq/L	3.5–5.0 mEq/L
Serum phosphorus	1.89 mg/dL	2.5–4.5 mg/dL
Vitamin D	3.1 ng/mL	30–100 ng/mL

Given the constellation of findings—cytopenia, hepatic dysfunction, premature greying, osteoporosis and neuropathy—a syndromic or genetic aetiology was suspected.

Clinical exome sequencing identified a monoallelic missense variant in the PARN gene (c.613T>C; p.Cys205Arg, exon 8). The identified missense variant alters a highly conserved residue and is predicted to be damaging to the protein function. However, the role of the variant in the disease could not be ascertained; therefore, it has been labelled as ‘Variant of Uncertain Significance’. Although the pathogenicity of this specific variant remains uncertain, the involvement of PARN and the patient’s clinical features are consistent with the spectrum of TBD.

Differential diagnosis

The patient’s presentation with pancytopenia, weight loss, premature greying and fatigue raised suspicion for haematologic, nutritional and autoimmune disorders. A markedly low reticulocyte count pointed toward ineffective erythropoiesis, leading to initial consideration of nutrient deficiencies and marrow failure syndromes.

Severe vitamin B₁₂ deficiency was confirmed early and accounted for several features, supported by bone marrow evidence of ineffective erythropoiesis. However, even after correcting the deficiencies, the systemic dysfunction remained disproportionate and persistent.

An immune-mediated process was briefly considered due to a positive DAT and elevated inflammatory markers. Yet, the absence of haemolysis, negative autoimmune serologies and lack of systemic features argued against autoimmune cytopenia or connective tissue disease.

Hepatic fibrosis (HF) lacked a clear aetiology, with autoimmune and infectious causes excluded. The unique constellation of premature ageing features, persistent cytopenia and fibrotic involvement of the lungs and liver in a young adult shifted clinical suspicion toward a cryptic inherited disorder. Although the absence of a family history initially argued against hereditary syndrome, a de novo mutation remained a possibility.

This led to the hypothesis of a TBD which can mimic acquired conditions and present with variable penetrance. Though rare, it may lack the classical mucocutaneous triad of DC and instead manifest subtly with marrow failure, organ fibrosis and features of accelerated ageing.

This was substantiated by genetic analysis, which identified a pathogenic monoallelic variant in the PARN gene, providing a unifying explanation for the constellation of her clinical features.

Treatment

The patient was treated with intravenous cyanocobalamin 1000 µg daily for 5 days, then weekly for 4 weeks, followed by monthly maintenance to correct severe deficiency.

Supportive treatment included whole blood transfusions for symptomatic anaemia, oral folic acid (1 mg daily) and vitamin D (60 000 IU weekly) with elemental calcium (1000 mg daily) for osteoporosis. Electrolyte imbalances were corrected with standard supplementation.

She also underwent physiotherapy, and her family received genetic counselling following diagnosis of a TBD.

Outcome and follow-up

The patient showed symptomatic improvement following correction of deficiencies and supportive care. During the 2-week follow-up, her blood counts were stable, fatigue improved and no new clinical concerns were reported.

She continues to receive regular outpatient follow-up for surveillance of hepatic and pulmonary function and to monitor the progression of bone marrow or systemic involvement.

Discussion

Telomeres, which are repetitive DNA sequences capping chromosome ends, preserve genomic integrity by shielding chromosomes from degradation. With each cell division, telomeres shorten, eventually reaching a critical length that triggers cellular senescence or apoptosis.⁵ Under physiological conditions, the enzyme telomerase, a ribonucleoprotein complex that includes telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), maintains telomere length through elongation. However, pathogenic variants in genes encoding components of the telomerase complex impair this enzyme’s function, leading to premature telomere attrition, resulting in a group of inherited conditions called TBD.⁶

X-linked recessive pathogenic variants in DKC1 first established the link between DC and markedly short telomeres, making DC the prototypical TBD.^{7 8} DC is classically defined by the mucocutaneous triad of oral leukoplakia, nail dystrophy and reticular skin pigmentation, or by two of these features with bone marrow failure syndrome (BMFS). Other recognised manifestations include idiopathic pulmonary fibrosis (IPF), HF and an increased risk of haematological and solid malignancies.⁹ Severe childhood-onset TBD subtypes—such as HH syndrome, Revesz syndrome and Coats plus syndrome—also result from variants in genes implicated in DC.²

TBDs may present with isolated mucocutaneous, organ-specific or haematological involvement and may manifest in adulthood without the classical DC triad. Typically, the inherited defect is masked by conditions such as aplastic anaemia, BMFS, IPF, or HF and gastrointestinal diseases.¹⁰ Without the classical triad and due to delayed clinical presentation, these patients are frequently misdiagnosed, especially when not seen in specialised centres. Monoallelic variants in TERT, TERC and RTEL1 are typically identified in TBDs, often presenting as IPF or BMFS.^{11 12}

The PARN gene, which belongs to a highly conserved family of exoribonucleases, acts by shortening mRNA poly(A) tail length through the process of deadenylation, thus regulating gene expression.¹³ Deep sequencing of TERC RNA 3-prime terminal showed that PARN is required for the removal of post-transcriptionally acquired oligo(A) tails that target nuclear RNAs for degradation, which is required for the 3-prime-end maturation of the TERC.¹⁴

PARN is among the 20% of genes least tolerant to rare, disruptive variants, supporting its essential role and the concept of haploinsufficiency in carriers.¹⁵ Germline pathogenic variations in PARN are recognised causes of dyskeratosis congenita, autosomal recessive 6 (DKCB6), and the broader spectrum of DC/TBD. Biallelic PARN variants were reported in cases of HH syndrome.¹³ Monoallelic germline pathogenic variants have been implicated in telomere-related PFBMFT4. The initial link between PARN and IPF came from the identification of novel monoallelic variants, and subsequent studies have reported monoallelic PARN rare variants in five out of 262 patients with sporadic IPF who underwent whole-exome sequencing, establishing an emerging association that has now been documented in over 65 cases in the literature.15,17 However, the complete range of clinical features associated with PARN mutations remains poorly understood due to the limited number of reported cases.

Notably, our patient harboured a monoallelic missense variant in PARN, c.613T>C (p.Cys205Arg), affecting a highly conserved residue within the R3H domain (residues 178–245). The variant is predicted to have a deleterious functional effect by four of five in silico missense prediction tools (LRT, Mutation Assessor, MutationTaster and SIFT). When evaluated using the ACMG/AMP standards for variant classification, this variant meets several supportive criteria: PM1—the substitution occurs within a critical and well-established functional domain (R3H domain) with no known benign variation. PM2—the variant is absent or extremely rare in population databases. PP3—multiple computational tools predict a damaging effect on the gene or gene product. PP2—PARN is a gene with a low rate of benign missense variation and in which missense variants are a common mechanism of disease.¹⁸ Although its clinical significance remains uncertain, its potential relevance to TBDs is supported by the gene’s established role and by parallels with other PARN missense variants—such as p.Lys59Arg (ClinVar ID: VCV000424063.2) and p.Ala383Val (ClinVar ID: VCV000180661.1)—which are reported as ‘likely pathogenic’ in the ClinVar database.^{19 20}

Multiple genes, variable inheritance, incomplete penetrance and somatic genetic rescue can differentially affect organ systems in TBDs. Additionally, environmental and lifestyle factors can variably influence the replicative capacity of different organ systems.¹² In the context of our patient, these complexities may explain the observed phenotype, despite only a monoallelic PARN variant being identified.

Although monoallelic PARN mutations are more commonly associated with IPF rather than primary haematological manifestations, the presence of cytopenia in our patient raises the possibility of an underlying TBD that may render the bone marrow more susceptible to haematopoietic stress, such as severe vitamin B₁₂ deficiency. Telomere shortening compromises the replicative potential of haematopoietic stem cells, leading to accelerated cellular senescence and an increased risk of BMFS.¹⁶ While the cytopenia observed in our patient was most likely attributable to severe vitamin B₁₂ deficiency, the presence of a PARN variant underscores the importance of ongoing clinical and haematological monitoring to assess for any evolving marrow failure phenotype in this genetically predisposed individual.

Cirrhosis in TBD has often been under-recognised; however, emerging evidence suggests it may be more prevalent than previously appreciated. A retrospective analysis from the Aachen Telomere Biology Disease Registry using transient elastography found that 88.8% of adult patients with pathogenic TERC or TERT mutations had at least moderate HF, and 33.3% had cirrhosis.²¹ A comparable case in the literature described a patient with pancytopenia and HF carrying monoallelic variants in both PARN (c.1613C>G) and TERT (c.2476G>A).²² In contrast, our patient harboured only a monoallelic PARN mutation yet developed both hepatic and pulmonary fibrosis. Although monoallelic PARN is commonly associated with IPF, its downstream impact on telomerase function may account for HF typically seen with TERT or TERC mutations. These findings support an expanding clinical spectrum of PARN-associated TBDs and underscore the importance of considering HF as part of its phenotype.

The gold standard for diagnosing suspected TBD includes genetic testing through next-generation sequencing and flow cytometry-based fluorescence in situ hybridisation assays to measure telomere length. Treatment is currently supportive and tailored to symptom severity, organ transplantation needs and risk factor mitigation, although haematopoietic stem cell transplantation can be potentially curative in patients with haematologic manifestations.^{23 24} While some preclinical and small clinical studies suggest telomere elongation with androgens like danazol and nandrolone, the long-term effects remain unknown.^{25 26}

Our patient presented with features of TBD, HF and IPF. Following a systematic evaluation that excluded other common causes, whole-exome sequencing identified the culprit gene, and an extensive literature search enriched our understanding of this rare presentation. She was managed supportively, with genetic counselling provided to her family. She understood the nature of her condition and accepted that curative options were not feasible. At her 2-week follow-up, her blood counts remained stable, and there were no new signs of clinical deterioration.

Patient’s perspective.

I was feeling weak and tired for many years and had stopped going out of the house. I had lost weight and had a very minimal appetite. I felt breathless just walking a little. I left my job due to this. My hair was turning grey, and my whole body kept aching. I decided to get basic tests done, which showed that I had very little blood in my body, so I consulted the doctor and got admitted. When I came to the hospital, I was scared. I was expecting that all this was because of my poor diet habits, but later doctors explained to me that apart from deficiencies, I also have a rare genetic condition called cryptic dyskeratosis congenita. It was making my cells start aging or getting damaged too early for my age. That’s why I had issues like fewer blood cells, a damaged liver, lungs, and bones. Doctors counseled that there’s no complete cure yet, but there are ways to manage the symptoms and protect my organs. It was a lot to take in, but slowly, since my condition has improved; I have come to accept my condition.

Learning points.

• The clinical presentation of rare disorders like telomere biology disorder (TBD) can present in adulthood with subtle, oligosymptomatic features such as isolated cytopenias, hepatic or pulmonary fibrosis, without the classical mucocutaneous triad of dyskeratosis congenita.

• Genotype–phenotype correlation in TBDs is often challenging due to incomplete penetrance, variable expressivity and modifying effects of environmental or acquired factors.

• A monoallelic variant in a telomere-associated gene like PARN, even if classified as a variant of uncertain significance, may hold clinical relevance when supported by phenotypic overlap and pathophysiologic plausibility.

• Systematic and timely pursuit of targeted diagnostics such as genetic testing, guided by clinical acumen and a high index of suspicion, reflects prudent medical practice when evaluating atypical presentations and can significantly impact prognosis and management.