Aortic coarctation and McArdle disease in histiocytosis-lymphadenopathy plus syndrome: expanding the SLC29A3 spectrum

Abstract

Histiocytosis-lymphadenopathy plus syndrome (HLPS) is a rare inherited disorder caused by SLC29A3 variants. We report 2 Pakistani brothers with HLPS and markedly different clinical features despite identical genotypes. The 15-year-old had severe growth failure, facial dysmorphism, insulin-dependent diabetes, hypogonadotropic hypogonadism, and coarctation of the aorta (CoA) requiring balloon dilatation. Genetic testing identified SLC29A3 and PYGM variants, indicating concurrent HLPS and McArdle disease. His 20-year-old brother had insulin-dependent diabetes and celiac disease from age 3, later developing hypertension, proteinuria, and characteristic skin changes. This case highlights marked intrafamilial variability in HLPS and identifies CoA as a rare cardiovascular feature. It also supports comprehensive genetic testing in patients with early-onset diabetes and multisystem disease.

Introduction

Histiocytosis-lymphadenopathy plus syndrome (HLPS) is a rare autosomal recessive disorder caused by pathogenic SLC29A3 variants, encoding human equilibrative nucleoside transporter 3 (hENT3), which maintains lysosomal integrity, immune homeostasis, and phagolysosomal function [1]. SLC29A3 also supports antibacterial signaling in dendritic cells and transcription factor EB-mediated autophagy, contributing to the hyperinflammation and immunodeficiency seen in SLC29A3 disorders [2]. Loss of hENT3 function additionally triggers a T-cell receptor 7/8-dependent stress response implicated in histiocytosis in murine models [3].

The SLC29A3 spectrum includes H syndrome, Faisalabad histiocytosis, and familial Rosai-Dorfman disease, reflecting overlapping phenotypes [4]. A systematic review identified hyperpigmentation, hypertrichosis, insulin-dependent diabetes mellitus (IDDM), short stature, and hypogonadism as common manifestations [5, 6]. Renal manifestations, including proteinuria, hematuria [7] have also been reported, supporting periodic renal surveillance [1, 7]. IDDM in HLPS is thought to result from chronic inflammatory β-cell injury, potentially mediated by macrophage-derived cytokines, although the exact mechanism remains incompletely understood [8].

HLPS can mimic endocrine, rheumatologic, and immunologic disorders [9], with reported misdiagnoses including cryopyrin-associated periodic syndrome [10] and systemic juvenile idiopathic arthritis [11].

McArdle disease is an AR metabolic myopathy caused by pathogenic PYGM variants resulting in skeletal muscle glycogen phosphorylase deficiency and impaired glycogen breakdown, leading to exercise intolerance, fatigue, muscle cramps, myoglobinuria, and rhabdomyolysis [12], while extramuscular manifestations are uncommon [12, 13].

We report 2 brothers with HLPS who presented with severe growth failure, IDDM, and multisystem involvement, including coarctation of the aorta (CoA) in the younger brother. Genetic testing identified biallelic pathogenic SLC29A3 variants and a concurrent PYGM variant. These cases highlight the phenotypic and genetic heterogeneity of HLPS.

Case presentation

Case 1

A 15-year-old boy, a known case of IDDM and celiac disease (proven by positive anti-tissue transglutaminase serology) since the age of 8 years, presented to Aga Khan University Hospital (AKUH) with concerns of short stature and stunted growth. He also reported bilateral knee pain, stiffness of the small joints of the hands, and facial swelling upon waking. He was being managed at local clinics/hospitals with basal bolus regime via multiple daily injection (MDI) therapy with insulin for IDDM.

Case 2

A 20-year-old male, elder brother of the index patient, with IDDM and celiac disease diagnosed at age 3, presented to the AKUH endocrinology clinic for routine management. He was on MDI for insulin managed locally, with fluctuating home glucose levels and partial dietary adherence. He denied recent hypoglycemia, visual disturbances, or gastrointestinal symptoms.

Diagnostic assessment

Case 1

Previous laboratory investigations conducted outside AKUH showed a low insulin-like growth factor-1 (IGF-1) level of 36.29 ng/mL (SI: 81.54 pmol/L) (reference: 201-609 ng/mL [SI: 451.65-1368.4 pmol/L]). Autoimmune screening revealed a negative antinuclear antibody profile, anti dsDNA and anti-GAD 65 autoantibodies. Thyroid-stimulating hormone was 4.051 µIU/mL (SI: 4.051 mIU/L) (normal: 0.7-6.4 µIU/mL [SI: 0.7-6.4 mIU/L]).

On examination, his weight was 24.5 kg (z score −5.88) and height 118 cm (z score −6.79) (Fig. 1). He was hypertensive (148/89 mmHg), with a pulse rate of 108/min and radio-femoral delay. Dysmorphic features included coarse facial features, puffy face, prominent eyes, synophrys, high-arched palate, depressed nasal bridge, and camptodactyly. Extensive symmetrical areas of hyperpigmentation, induration, and hypertrichosis involved the shins (Figs. 2-4), chest, and inguinal region. Genital examination revealed prepubertal phallic length and testicular volume, with rubbery bilateral testes and sexual maturity rating (SMR) Tanner stage I. A systolic ejection murmur over the left sternal border raised suspicion of CoA. These dysmorphic features prompted suspicion of genetically mediated diabetes.

Figure 1.

Growth chart of patient 1 showing his height and weight over follow-up period.

Figure 2.

Right ankle and shin of patient 1.

Figure 4.

Bilateral posterior legs and ankles of patient 1.

Figure 3.

Left ankle and shin of patient 1.

Further evaluation revealed poor glycemic control hemoglobin A1c (HbA1c) of 10.8%; random blood glucose levels frequently >300 mg/dL (SI: >16.65 mmol/L). Renal evaluation showed a spot urine albumin-to-creatinine ratio of 1.9 mg/g (SI: 0.21 mg/mmol) (normal: <30 mg/g [SI: <3.4 mg/mmol]). Hematological investigations demonstrated anemia hemoglobin 8.6 g/dL (SI: 86 g/L) (normal: 12.3-16.6 g/dL [SI:123-166 g/L]), mean corpuscular volume 64 fL (reference: 78.7-96.3 fL). Hormonal assessment confirmed hypogonadotropic hypogonadism, with follicle-stimulating hormone (FSH) of 1.5 mIU/mL (SI: 1.5 IU/L) (normal: 0-10 mIU/Ml [SI: 0-10 IU/L]), luteinizing hormone (LH) of 0.12 mIU/mL (SI: 0.12 IU/L) (normal: 1.2-7.8 mIU/Ml [SI: 1.2-7.8 IU/L]), and testosterone of 0.24 ng/dL (SI: 0.01 nmol/L) (normal:5-800 ng/dL [SI: 0.17-27.76 nmol/L]). The 8-Am serum cortisol was within normal limits.

Bone age assessment demonstrated a bone age of 12 years and 6 months compared with a chronological age of 17 years and 3 months, consistent with a marked delay in skeletal maturation. Ultrasound of the testes revealed diffuse scrotal wall thickening (45 mm) with markedly increased vascularity; both testes had an estimated volume of 2 mL. His electrocardiography was normal with sinus rhythm, but his echocardiogram revealed CoA distal to brachiocephalic trunk.

Case 2

On physical examination, his weight was 41 kg (z score −4.2) and height 151 cm (z score −4.4), with a blood pressure of 130/86 mmHg and a pulse rate of 108. Examination revealed similar facial and cutaneous features as his younger brother. Moreover, genital examination revealed prepubertal phallic length and testicular volume with rubbery texture of bilateral testes with SMR corresponding to Tanner stage I and a right-sided testicular swelling.

Following initial clinical assessment, the patient underwent further laboratory evaluation which demonstrated poor glycemic control (HbA1c 9.4%), significant proteinuria with a spot urine albumin-to-creatinine ratio of 2659 mg/g (SI: 300.8 mg/mmol). IGF-1 measurement was not performed in this patient since he was 20-years-old at presentation with no history or clinical concern of short stature, and evaluation was focused on diabetes management.

Treatment

Case 1

He was started on ramipril 5 mg once daily for hypertension and proteinuria, and his insulin regimen was intensified. Moreover, blood samples were sent for whole-exome sequencing (WES) given the dysmorphic features.

Case 2

In view of elevated blood pressure, he was initiated on ramipril 5 mg once daily, and his insulin regimen was intensified.

Outcome and follow-up

Case 1

Despite markedly low IGF-1, growth hormone (GH) deficiency was not diagnosed, as this was attributed to chronic systemic illness and suspected HLPS. Repeat IGF-1 or GH stimulation testing was not pursued because it was unlikely to alter diagnosis or management.

WES identified HLPS associated with a pathogenic SLC29A3 variant (c.300+1G>A) and McArdle disease due to a likely pathogenic PYGM variant (c.1220T>C; p.Ile407Thr). The PYGM variant was classified as likely pathogenic based on variant interpretation and genotype–phenotype correlation. However, the patient lacked typical McArdle manifestations, including exercise-induced cramps, myoglobinuria, rhabdomyolysis, or cardiomyopathy, arguing against clinically manifest McArdle disease. In contrast, the patient's major manifestations were more consistent with HLPS.

Subsequently, the patient underwent balloon dilatation and valvuloplasty for correction of CoA and replacement of iron levels. He continues to be followed regularly by endocrinology and cardiology team, for his IDDM and any exercise intolerance.

Case 2

He also underwent psychiatric evaluation for anxiety, low mood, sleep disturbance, and subjective memory difficulties. He was diagnosed with a mood disorder with bipolar-spectrum features and started on fluoxetine 20 mg and risperidone 1 mg once daily.

Following his brother's HLPS diagnosis, the family received genetic counseling, and testing revealed homozygosity for the same pathogenic SLC29A3 splice-site variant. He continues regular adult endocrinology follow-up for IDDM and hypertension.

Discussion

This case series describes 2 brothers with genetically confirmed HLPS who, despite sharing the same pathogenic SLC29A3 variant, exhibited marked intrafamilial phenotypic variability [4]. These cases expand the known cardiovascular phenotype of HLPS.

Both siblings developed IDDM in early childhood, which is consistently reported across the SLC29A3 spectrum [14, 15], which was initially managed as an isolated autoimmune condition, with no early suspicion of an underlying syndromic diagnosis [16]. This delay is representative of the broader diagnostic challenge in HLPS, where symptoms develop gradually over years.

Hamsho et al documented a male with primary hypogonadism, GH deficiency, and hyperglycemia [17] which is similar to the younger brother who demonstrated a more extensive phenotype with severe growth failure (height 118 cm at age 15), supporting the concept that growth impairment in HLPS is multifactorial and may reflect chronic inflammation, metabolic dysregulation, and impaired IGF-1 signaling rather than isolated endocrine deficiency [18].

Recombinant human GH therapy has been reported rarely in SLC29A3-related disease, with no dedicated trials assessing efficacy. Jacquot et al reported a 2-year-old female treated with tocilizumab and GH for endocrine involvement [19], with accelerated growth velocity; however, concurrent inflammatory control limits attribution to GH alone. While selected patients may achieve short-term growth benefits, evidence does not demonstrate consistent normalization of adult height [20], and GH therapy remains experimental and individualized.

Emerging therapies increasingly target inflammatory and mitogen-activated protein kinase (MAPK) pathways rather than endocrine replacement alone. Tocilizumab, an IL-6 receptor antagonist, has improved systemic inflammation and skin manifestations in reported H syndrome cases [19, 21], although neurologic or fibrotic manifestations may persist [20]. Similarly, MAPK kinase (MEK) inhibition has been explored in refractory histiocytic disease. A reported HLPS case with a CNS dural-based inflammatory pseudotumor showed clinical and radiologic improvement with cobimetinib, supporting MEK inhibition in selected severe or refractory phenotypes [22].

The younger sibling was found to have CoA, which to our knowledge has not been previously described in HLPS. Cardiovascular involvement in SLC29A3 disorders has been scarcely reported and has been limited to nonspecific descriptions such as valve dysfunction [23].

Genital involvement, including scrotal wall thickening and testicular atrophy, occurred in both siblings [17]. Although HLPS-associated hypogonadism is typically hypergonadotropic due to testicular histiocytic infiltration [17], the younger brother had low LH, FSH, and testosterone, consistent with hypogonadotropic hypogonadism. Despite chronic illness potentially suppressing the hypothalamic–pituitary–gonadal axis, marked testicular atrophy with low gonadotropins supports true central hypogonadism. Gonadotropins were not measured in the older brother, precluding classification. Risperidone had been started <1 year earlier, making it unlikely to explain his longstanding pubertal delay; prolactin was not measured due to financial constraints [24]. Testosterone was not initiated because diabetes and renal complications required priority management.

Proteinuria and hematuria have been reported in HLPS [1, 7], including persistent cases without alternative causes, supporting intrinsic renal involvement [7]. In our patients, however, proteinuria is more likely multifactorial, given longstanding poorly controlled IDDM, hypertension, and diabetic microvascular complications. Nevertheless, HLPS may have contributed to or exacerbated the renal phenotype.

Both brothers had celiac disease, an association rarely discussed in the SLC29A3 literature. This raises the possibility that celiac disease may represent part of the broader autoimmune predisposition associated with SLC29A3 mutations. However, evaluation for pancreatic islet autoimmunity in the context of IDDM was limited to anti-GAD65 antibodies only, and comprehensive autoantibody panels were not performed [25], which limits definitive classification of the diabetes as autoimmune in origin [8].

The younger brother also had a concurrent molecular diagnosis of McArdle disease, illustrating multilocus genomic disorders [26, 27], and particularly in consanguineous families where homozygosity for multiple recessive variants is more likely. This diagnosis enables counseling on exercise tolerance, avoidance of intense anaerobic activity, pre-exercise carbohydrate intake, and recognition of the “second wind” phenomenon [28].

Learning points

• Coarctation of the aorta expands the cardiovascular spectrum of HLPS supporting cardiac screening.

• Concurrent HLPS and McArdle disease highlights genomic complexity.

• Consider HLPS with early-onset diabetes, growth failure, cutaneous/genital abnormalities, or renal involvement.

• Early molecular diagnosis enables multisystem surveillance and genetic counseling.

Contributors

All authors made individual contributions to authorship. B.R., M.N.S., S.K., and M.A.: diagnosis and management of the patient, and conceptualization of the article. S.M.D.H.: conceptualization, data collection, and manuscript writing. S.K. and M.A.: supervision of the article. All authors reviewed and approved the final draft.

Funding

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosures

The authors declare no competing interests.

Informed patient consent for publication

Signed informed consent obtained directly from the patient's relatives or guardians for Case 1. For Case 2, signed informed consent obtained directly from the patient.

Data availability

The original contributions presented in this study are included in the article.