Late Diagnosis of Transaldolase Deficiency in an Adult Male with Hypergonadotropic Hypogonadism

Abstract

Transaldolase deficiency is a rare autosomal recessive disorder of the pentose phosphate pathway, most often recognized in infancy or early childhood due to severe hepatic or hematologic manifestations. We describe the case of a 33-year-old man whose diagnosis emerged only in adulthood, following a prolonged and fragmented journey across multiple specialties. His presentation included hypergonadotrophic hypogonadism, persistent cytopenias, splenomegaly, and subtle but persistent cardiac anomalies. The eventual diagnosis was secured through genetic testing, which identified a homozygous pathogenic variant in the TALDO1 gene. This case highlights that transaldolase deficiency may manifest beyond childhood with insidious, multisystem involvement. It underscores the critical value of coupling meticulous clinical observation with targeted genetic testing in unveiling rare but clinically meaningful diagnoses.

Keywords

transaldolase deficiency - pentose phosphate pathway - inborn errors of metabolism - hypergonadotrophic hypogonadism - homozygous mutation - genetic

Introduction

Transaldolase deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the TALDO1 gene, which encodes a key enzyme in the nonoxidative branch of the pentose phosphate pathway.[1] Disruption of this pathway leads to the accumulation of polyols in body fluids and failure to produce NADPH and glutathione contributing to dysfunction across various organ systems.[2] While severe neonatal forms present with hepatosplenomegaly and liver failure, milder or atypical forms may manifest later in life with less specific signs. Hematologic and immunologic features, including splenomegaly and bone marrow hypoplasia, can precede overt endocrine manifestations. Cardiac anomalies such as bicuspid aortic valve and great vessel dilatation may form part of the clinical spectrum. In adults presenting with hypergonadotrophic hypogonadism in combination with persistent cytopenias or immune abnormalities, clinicians should maintain a high index of suspicion for underlying metabolic disorders. Misdiagnosis or delayed recognition is common when symptoms are evaluated in isolation. Hypergonadotrophic hypogonadism is a recognized feature of this condition and, when present alongside other systemic findings, can guide clinicians toward diagnosis.

Case Presentation

A 33-year-old Emirati man was first referred to the hematology clinic in 2015, at the age of 24 years, following the incidental detection of pancytopenia during routine screening for national service. He did not recall any significant childhood infections and had no history of hospital admissions for infectious illnesses. At presentation, his main complaint was recurrent upper respiratory tract infections, occurring approximately four to six times per year, most commonly pharyngitis and bronchitis. These episodes resolved uneventfully within a normal duration of illness and were not associated with chronic cough or purulent sputum production. He denied any history of pneumonia, skin infections, diarrhea, joint pain, or weight loss. His appetite was good and his weight was stable.

In his past medical history, he had been evaluated at the age of 19 years in another facility for delayed puberty and was diagnosed with hypergonadotrophic hypogonadism. Testosterone replacement therapy was initiated, which he took intermittently for 2 years before discontinuing follow-up.

On examination at the age of 24 years, his body weight was 62 kg, height 169 cm, with a body mass index of 21.71 kg/m². He appeared lean, with an elongated thin face and a narrow chest. Abdominal examination revealed splenomegaly palpable on deep inspiration, without hepatomegaly. There were no dysmorphic features or lymphadenopathy. Pubertal assessment showed Tanner stage II development, with bilaterally small and firm testes.

Initial investigation ([Table 1]) revealed pancytopenia and low immunoglobulin levels (low IgA and low IgM). Bone marrow biopsy in 2017 demonstrated moderately to markedly hypocellular marrow with maturing trilineage hematopoiesis, without morphological features suggestive of myelodysplastic syndrome or lymphoproliferative disorders. Further workup ([Supplementary Table S1], available in online version only) by immunology and hematology teams, including immunoglobulin subtyping and flow cytometry confirmed a state of immunodeficiency after ruling out secondary causes. Based on these findings, he was diagnosed with an incomplete form of common variable immunodeficiency (CVID) according to the established diagnostic criteria of markedly reduced IgG with low IgA and/or IgM, poor or absent vaccine response, and absence of other defined immunodeficiency states.

Table 1 Investigations

Domain	Findings
Hematology	WBC: 2.9–3.1 × 109/L (NR = 4.5–11); Hb: 10.3 g/dL (NR = 13.2–17.3); platelets: 98–119 × 109/L (NR = 140–400)
Immunology	IgA < 0.5 g/L (NR = 0.7–4); IgM 0.26 g/L (NR = 0.4–2.4); IgG 9.09 g/L (NR = 7–16) → CVID-like profile
Bone marrow	Hypocellular trilineage hematopoiesis; no dysplasia or clonal abnormality
Hepatology	Splenomegaly (21 cm), mild hepatomegaly (16 cm), normal liver echotexture and hemodynamics, cholelithiasis present
Renal	Creatinine 115.5 µmol/L (NR = 53–115); eGFR 77 mL/min/1.73 m2 (>60); protein/creatinine ratio 0.41 g/g (<0.2); albuminuria 12.77 mg/mmol (<3); kidneys normal on ultrasound
Cardiac	Bicuspid aortic valve; aortic root 3.69 cm; dilated pulmonary trunk 4.09 cm
Endocrine	LH 92.2 mIU/mL (NR < 8.6); FSH 153 mIU/mL (NR = 1.5–12.4); testosterone 0.49 nmol/L (NR = 6.6–31) → hypergonadotrophic hypogonadism; DEXA: Z-scores –3 (lumbar spine), –1 (total hip)
Genetics	TALDO1 homozygous mutation (c.304C > T; p.Arg102*)

Abbreviations: CVID, common variable immunodeficiency; DEXA, dual-energy X-ray absorptiometry; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; Ig, immunoglobulin; LH, luteinizing hormone; NR, normal range; TALDO1, transaldolase 1; WBC, white blood cell count.

Additional investigations revealed normal liver function enzymes but an elevated unconjugated bilirubin of 56 μmol/L (reference range: 5–22) with normal direct bilirubin which was thought to be related to Gilbert's syndrome. Abdominal ultrasonography showed splenomegaly measuring 21 cm in long axis, a liver long axis of 16 cm with homogeneous texture and no focal lesions, and no evidence of gallbladder wall thickening or pancreatic abnormalities.

His initial renal function revealed evidence of albuminuria with normal renal imaging ([Table 1]). Over time, his renal function declined, with the latest estimated glomerular filtration rate ranging between 62 and 68 mL/min/1.73 m². Cardiac assessment for complaint of short-term palpitations was done in 2018, which showed sinus rhythm on electrocardiogram. Echocardiography demonstrated a bicuspid aortic valve, dilatation of the proximal ascending aorta to 36.9 mm, and pulmonary trunk dilatation. No atrial septal defect or right ventricular dilatation was seen. Computed tomography angiography confirmed dilatation of the ascending aorta and pulmonary trunk, with a maximum pulmonary trunk diameter of 40.9 mm.

From an endocrinology perspective, further assessment confirmed persistent hypergonadotrophic hypogonadism with a normal male karyotype (46,XY). A dual-energy X-ray absorptiometry (DEXA) scan in 2018 revealed low bone mineral density for age, with Z-scores of –3 at the lumbar spine and –1 at the total hip. Testosterone replacement therapy was reinitiated, and a repeat DEXA scan in 2023 showed improvement, with Z-scores of –1.6 at the lumbar spine and –1 at the total hip.

In 2025, during follow-up in the endocrinology clinic, the constellation of unexplained hypergonadotrophic hypogonadism, pancytopenia, splenomegaly, cardiovascular abnormalities, and hepatic involvement prompted referral to the genetics clinic for further evaluation. This decision was also informed by the presence of similar cases within the institution. Genetic testing with whole-genome sequencing (the first-line modality in our institution) revealed a homozygous likely pathogenic variant (based on The American College of Medical Genetics and Genomics recommendation) in the TALDO1 gene (c.304C > T; p.Arg102*), confirming the diagnosis of transaldolase deficiency, a rare multisystem disorder.

The patient was continued on intramuscular testosterone undecanoate (Nebido 750 mg every 3 months) for which the patient reported significant improvement in energy levels, mood, and physical function, along with progression of secondary sexual characteristics. According to the patient, no semen analysis had been performed in the previous hospitals before starting testosterone therapy. During his evaluation at our institution, he expressed no interest in exploring fertility options and chose to proceed only with testosterone replacement to manage his symptoms and maintain secondary sexual characteristics. Over the years, the frequency of infections declined, bone mineral density improved, and blood counts remained stable. Serial imaging demonstrated no progression of aortic dilatation and latest liver ultrasound showed no lesions. He continues to receive coordinated multidisciplinary care with regular follow-up in hematology, endocrinology, cardiology, hepatology, and nephrology teams.

Discussion

This case exemplifies how rare metabolic diseases may remain unrecognized into adulthood when clinical signs are mild or appear unrelated. The patient's delayed puberty, immune dysfunction, cytopenias, and cardiac anomalies were investigated independently, but only genetic testing revealed the unifying diagnosis of transaldolase deficiency.

Transaldolase deficiency is an ultrarare autosomal recessive disorder of the pentose phosphate pathway, characterized by a wide spectrum of multisystemic manifestations. It was first described in 2001 in a patient with neonatal liver failure and has since been associated with clinical features including intrauterine growth restriction (IUGR), hepatosplenomegaly, cytopenia, cardiac defects, immunodeficiency, and, more recently, endocrine abnormalities such as hypergonadotrophic hypogonadism.[3] [4]

In our case, the diagnosis of transaldolase deficiency was considerably delayed, despite the presence of hallmark features—namely splenomegaly, bone marrow suppression, cardiac anomalies (including a bicuspid aortic valve and a dilated pulmonary trunk), and endocrine dysfunction. The recognition of hypergonadotrophic hypogonadism prompted further workup, culminating in genetic confirmation of a homozygous likely pathogenic TALDO1 variant (c.304C > T; p.Arg102*). This variant has not been widely reported but is consistent with the loss-of-function mutations described in previously documented patients.[5]

Recent literature, including a multicenter cohort of 34 individuals, confirms the heterogeneity of transaldolase deficiency. Patients may present at different stages of life. During the prenatal period, findings can include IUGR and/or oligohydramnios. In the neonatal stage, characteristic features often encompass dysmorphic facial traits, cardiovascular malformations, and hepato(spleno)megaly. Later in life, individuals may display a milder phenotype or remain entirely asymptomatic.[6] There is currently no clear genotype–phenotype correlation, largely because of the limited number of reported cases and the small spectrum of identified mutations. Considerable phenotypic variability has also been noted among affected members of the same family. Although certain mutations may be associated with either an early or late clinical presentation, this observation remains preliminary and requires validation through studies involving larger patient cohorts.[6]

In that cohort, 32% of patients exhibited external genital anomalies, whereas hypergonadotrophic hypogonadism was observed in 18% of cases—all in the early-onset phenotype.[6] Our patient's case contributes to the emerging evidence that this endocrine manifestation can also appear in individuals with a late-onset, milder disease trajectory, broadening the known phenotypic spectrum.

The mechanism underlying gonadal failure in transaldolase deficiency remains incompletely understood. Several hypotheses have been proposed. Transaldolase activity is essential for NADPH production and cellular redox balance. NADPH supports steroidogenesis and DNA/RNA synthesis in gonadal cells; therefore, its depletion may impair hormone biosynthesis.[6] In addition, toxic accumulation of polyols (e.g., sedoheptulose, xylitol) and reactive oxygen species (ROS) may lead to direct gonadal tissue damage and apoptosis, as supported by in vitro studies showing elevated ROS levels in patient-derived fibroblasts.[7]

Importantly, our patient also exhibited features mimicking CVID, with low IgA, IgM, and CD19+ B-cell counts. This immune profile has previously been described in other TALDO1-deficient individuals and reflects the profound metabolic disturbance caused by disruption of the pentose phosphate pathway. Impaired NADPH generation and antioxidant defense may contribute to both systemic manifestations and humoral immune defects, underscoring the need for immunologic evaluation in patients with suspected or confirmed transaldolase deficiency, even in the absence of recurrent or severe infections.[8]

Cardiac involvement is a recognized feature of transaldolase deficiency and is reported more frequently in children than in adults. In pediatric cases, congenital defects such as atrial septal defect, bicuspid aortic valve, aortic root or pulmonary artery dilatation, and valvular regurgitation are often described, frequently in association with hepatic, hematologic, and renal manifestations. Fewer structural abnormalities are documented in adults, which may reflect early detection and intervention in childhood or underrecognition later in life.[4] [9] These observations suggest a predominantly congenital origin, highlighting the importance of early and thorough cardiac evaluation as part of comprehensive care for affected individuals.

Skeletal involvement—another underrecognized facet of the disease—was also evident in our case. The patient had established low bone density by DEXA, which likely resulted from hypogonadism and chronic systemic illness. While short stature is frequently reported in affected individuals, our case demonstrated normal height but with compromised bone mineral density, further highlighting the variability in phenotypic expression.

Additionally, people with transaldolase deficiency may face a higher risk of developing liver cancer, particularly hepatocellular carcinoma. This is thought to be linked to long-standing oxidative stress and liver injury caused by disruption of the pentose phosphate pathway. Even when liver function appears stable, the risk can persist, making regular liver imaging and tumor marker checks an important part of ongoing care.[8]

Currently, there is no disease-specific therapy for transaldolase deficiency. Management remains supportive and organ-based. Hormonal replacement is indicated for pubertal induction and bone health maintenance. In general, fertility options in such cases are limited. Assisted reproductive procedures such as micro-TESE may be attempted if any residual spermatogenesis is present, whereas donor sperm insemination represents the most practical alternative when azoospermia is confirmed. Liver transplantation can be life-saving in transaldolase deficiency when severe liver failure, advanced fibrosis, or hepatocellular carcinoma are present. Reports show it restores liver function but does not reverse extrahepatic problems such as cardiac, renal, or endocrine involvement.[1] [10]

In our patient, renal involvement reflected the characteristic tubulopathy of transaldolase deficiency, marked by low–molecular-weight proteinuria, aminoaciduria, hypercalciuria, phosphate wasting, and hyperchloremic metabolic acidosis. These abnormalities, sometimes accompanied by structural renal changes, may progress to chronic kidney disease over time. The underlying mechanism is thought to involve intracellular accumulation of polyols and sugar phosphates, leading to tubular injury and dysfunction.[11]

Conclusion

This case underscores the importance of considering transaldolase deficiency in the differential diagnosis of adolescents and young adults with hypergonadotrophic hypogonadism and unexplained multisystem features. Several factors may underlie the delay in diagnosis. One major reason is the limited awareness of this disorder, given that it has only been characterized in recent years. In addition, the tendency of each speciality to concentrate on its respective organ system often leads to fragmented assessment and missed recognition of the overall clinical pattern. It is therefore essential to emphasize that the coexistence of multisystem involvement should raise clinical suspicion and prompt referral for genetic evaluation, even when TALDO1 deficiency is not initially considered. Early genetic testing in such contexts may help shorten the diagnostic odyssey and enable timely interventions and monitoring.

Conflict of Interest

The authors have nothing to disclose. ChatGPT (OpenAI, United States) was used exclusively for grammar and language correction. It did not contribute to data analysis, interpretation, or the generation of scientific content.

Acknowledgments

The authors express their gratitude to colleagues who participated in the care of the reported patient.

Patient Consent Statement

Verbal informed consent was obtained from the patient for publication of this case report.

Authors' Contributions

All authors were involved in data collection, manuscript drafting, and finalization. All authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.

Compliance with Ethical Principles

No ethical approval is required for a single case report.

Availability of Data and Material

For confidentiality reasons, the original data cannot be shared. However, all results are presented in this manuscript.

• References

• 1 Verhoeven NM, Huck JH, Roos B. et al. Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway. Am J Hum Genet 2001; 68 (05) 1086-1092
• 2 Wamelink MM, Struys EA, Jakobs C. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis 2008; 31 (06) 703-717
• 3 Zangen D, Florsheim N, Lavi E. et al. PMON193 reactive oxygen species in the development of gonadal failure in late-onset transaldolase deficiency. J Endocr Soc 2022; 6 (Suppl. 01) A621-A622
• 4 Yıldız M, Önal Z, Yeşil G. et al. A rare cause of hypergonadotropic hypogonadism: transaldolase deficiency in two siblings. J Clin Res Pediatr Endocrinol 2025; 17 (01) 97-102
• 5 Takaleh A, Abunamous N, AlShamsi A, Alhassani N, Almazrouei R. Hypergonadotropic hypogonadism due to transaldolase deficiency: two cases and literature review. JCEM Case Rep 2024; 2 (03) luae028
• 6 Williams M, Valayannopoulos V, Altassan R. et al. Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: update of 34 patients. J Inherit Metab Dis 2019; 42 (01) 147-158
• 7 Perl A. The pathogenesis of transaldolase deficiency. IUBMB Life 2007; 59 (06) 365-373
• 8 Cen K, Lu C. Prognostic and immune infiltration analysis of transaldolase 1 (TALDO1) in hepatocellular carcinoma. Int J Gen Med 2023; 16: 5779-5788
• 9 Al-Shamsi AM, Ben-Salem S, Hertecant J, Al-Jasmi F. Transaldolase deficiency caused by the homozygous p.R192C mutation of the TALDO1 gene in four Emirati patients with considerable phenotypic variability. Eur J Pediatr 2015; 174 (05) 661-668
• 10 Eyaid W, Al Harbi T, Anazi S. et al. Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype. J Inherit Metab Dis 2013; 36 (06) 997-1004
• 11 Loeffen YG, Biebuyck N, Wamelink MM. et al. Nephrological abnormalities in patients with transaldolase deficiency. Nephrol Dial Transplant 2012; 27 (08) 3224-3227

Publikationsverlauf

Artikel online veröffentlicht:
03. Dezember 2025