A rare case of H syndrome with severe multisystem involvement: Clinical challenges in low-resource healthcare settings

Abstract

H syndrome, a rare autosomal recessive disorder, is caused by pathogenic variants in the SLC29A3 gene located on chromosome 10q22. The clinical phenotype encompasses diverse manifestations, including hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, hyperglycemia with insulin-dependent diabetes mellitus, and hallux valgus/flexion contractures. A 20-year-old Syrian male born to consanguineous parents presented with fever, productive cough, chest pain, dyspnea, and scrotal discomfort. His medical history included progressive bilateral sensorineural hearing loss, failure to thrive, and significant short stature (height 1.46 m and weight 44 kg). Physical examination revealed conjunctival pallor, icterus, jugular vein distention, hypertrichosis, hypoplastic genitalia, and decreased breath sounds and dullness to percussion that were consistent with pneumonia and pleural effusion. Hormonal evaluation indicated primary hypogonadism and growth hormone deficiency. Echocardiography revealed pulmonary hypertension and tricuspid valve insufficiency. Chest imaging confirmed bilateral pleural effusion and lung infiltrates. The constellation of clinical findings, including hypogonadism, hypertrichosis, hallux valgus, and hepatosplenomegaly, collectively suggested H syndrome. The patient received supplemental oxygen therapy, resulting in improved oxygen saturation. Empirical antibiotic therapy consisting of intravenous ceftriaxone and levofloxacin was administered for 10 days, resulting in clinical improvement and resolution of respiratory symptoms. Given the high prevalence of this condition among consanguineous populations within resource-limited settings, this report emphasizes the critical need for accessible genetic testing and heightened clinical awareness of this rare disorder.

Introduction

H syndrome (HS), a rare autosomal recessive disorder, is caused by pathogenic variants in the SLC29A3 gene located on chromosome 10q22. It is histopathologically characterized by the presence of systemic histiocytosis.^1,2 A PubMed search using the keywords “H syndrome” and “SLC29A3” has indicated that approximately 130 cases of HS associated with SLC29A3 mutations have been reported in the literature up to October 2022. ³ The clinical phenotype encompasses diverse manifestations, many of which characteristically begin with the letter “H,” including hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, reduced height, hyperglycemia with insulin-dependent diabetes mellitus (IDDM), and hallux valgus/flexion contractures. ⁴ The diverse and progressive clinical symptoms of HS may mimic those of rheumatological diseases, resulting in diagnostic and treatment delays. ⁵ Recent literature suggests that early diagnosis and timely therapeutic intervention can alleviate certain clinical manifestations and help prevent disease progression. ⁶ This report describes a severe disease course of HS and details the patient’s clinical presentation, diagnostic challenges, therapeutic interventions, and clinical outcomes, with the aim of increasing awareness of this extremely rare and unique condition.

Case presentation

Chief complaints

A 20-year-old Syrian male with infantile habitus born to consanguineous parents presented with scrotal discomfort and a sensation of heaviness, fever, and productive cough of yellow sputum persisting for several days. He also reported a 1-month history of recurrent chest pain, which was exacerbated by recumbent positioning and associated with grade 2 exertional dyspnea.

Personal and medical history

The medical history of the patient included childhood-onset, bilateral progressive sensorineural hearing loss and failure to thrive, with persistent weight loss over several years. His body weight was 44 kg, height 1.46 m, and body mass index (BMI) 20.6 kg/m².

Physical examinations

His vital signs upon admission were as follows: blood pressure, 105/50 mmHg (13.9/6.6 kPa); pulse, 124 beats/min; tympanic temperature, 39°C (312.15 K); respiratory rate, 26 breaths/min; and oxygen saturation, 86% on room air. The clinical examination findings were as follows: conjunctival pallor, conjunctival icterus, jugular vein distention, hypertrichosis on the upper limbs and head, hippocratic fingers with mild peripheral cyanosis, and hallux valgus (Figure 1). Additional findings included short stature, prepubertal external genitalia with micropenis (penile length <1.5 cm), and a palpable scrotal mass (Figure 2). Abdominal examination showed hepatomegaly, splenomegaly, and hepatojugular reflux. Pulmonary examination revealed dullness to percussion extending to the fourth intercostal space on the right and bilateral basilar inspiratory crackles with diminished breath sounds on the right. Cardiac examination demonstrated distant heart sounds with murmurs audible in all precordial areas, most prominently in the tricuspid area. Skin examination revealed hyperpigmented plaques with well-demarcated borders and associated hypertrichosis, which initially affected the bilateral medial thighs and subsequently spread in a cephalad direction (Figure 3).

Figure 1.

Hallux valgus deformity observed in the patient.

Figure 2.

A micropenis (penile length <1.5 cm) with a palpable scrotal mass.

Figure 3.

Hypertrichosis and hyperpigmented plaques with clear borders extending upward from the inner thighs.

Echocardiography and laboratory examinations

Upon admission, comprehensive laboratory investigations were performed (Table 1). Growth hormone stimulation testing using arginine demonstrated severe growth hormone deficiency, with a baseline level of 0.7 μg/L that rose to 0.9 μg/L at 30 min, peaked at 5.0 μg/L at 60 min, and declined to 3.7 μg/L at 90 min (normal peak response ≥10 μg/L). Chromosomal analysis of leukocytes revealed a normal male karyotype (46XY). Hormonal evaluation indicated primary hypogonadism, characterized by markedly elevated gonadotropins (follicle stimulating hormone (FSH), 36.3 IU/L and luteinizing hormone (LH), 16.2 IU/L) and low testosterone levels (6.21 nmol/L; reference range, 8.4–28.8 nmol/L). Electrocardiography revealed irregular sinus rhythm with multiple ventricular extrasystoles displaying a bigeminal pattern, occasional missed beats, and QRS complex abnormalities (Figure 4).

Table 1.

Results of laboratory investigations conducted for the patient.

Test	Result	Unit	Reference range
White blood cells (WBC)	12.6	103/uL	04–10
Lymphocyte count	13.7	%	15–50
Granulocyte count	81.4	%	35–80
Lymphocyte count	1.7	109/L	0.8–4.0
Granulocyte count	10.2	109/L	2.0–7.8
Red blood cells (RBCs)	3.01	106/uL	4.5–5.5
Hemoglobin (HGB)	7.7	g/dL	11–16
Hematocrit (HCT)	23.6	%	37–54
Mean corpuscular volume (MCV)	78.3	fL	80–100
Mean corpuscular hemoglobin (MCH)	25.7	pg	27–34
Mean corpuscular hemoglobin concentration (MCHC)	32.8	g/dL	32–36
Red blood cell distribution width (RDW-CV)	16.8	%	11–16
Platelets (PLT)	297	103/uL	150–450
Mean platelet volume (MPV)	7.4	fL	08–11
Fasting blood glucose	91	mg/dL	70–110
Blood creatinine	0.6	mg/dL	0.2–1.3
Sodium (Na)	127	mEq/L	130–145
Potassium (K)	3.51	mEq/L	3.5–5.5

Figure 4.

Electrocardiographic (ECG) examination revealed irregular sinus rhythm with multiple ventricular extrasystoles displaying a bigeminal pattern, occasional missed beats, and QRS complex abnormalities.

Imaging examinations

Chest radiography revealed mediastinal widening, cardiomegaly with increased cardiothoracic ratio, bilateral pulmonary infiltrates throughout both lung fields, and a focal density overlying the right hemidiaphragm (Figure 5). Noncontrast chest computed tomography (CT) confirmed extensive bilateral pulmonary infiltrates consistent with pneumonia and bronchitis, accompanied by bilateral pleural effusions with right-sided predominance (Figure 6). Transthoracic echocardiography revealed pulmonary hypertension, severe tricuspid regurgitation, mild mitral regurgitation, and moderate pericardial effusion. Scrotal ultrasonography revealed a right inguinal hernia without signs of incarceration, a right-sided hydrocele with a diameter of 82 mm with anechoic contents, and significant soft tissue edema involving the bilateral inguinal regions and scrotal walls, more pronounced on the right side (Figure 7).

Figure 5.

Chest radiography demonstrated mediastinal widening, cardiomegaly with increased cardiothoracic ratio, bilateral pulmonary infiltrates throughout both lung fields, and a focal density overlying the right hemidiaphragm.

Figure 6.

Noncontrast chest computed tomography (CT). (a) Axial section of the upper pulmonary lobes showing multiple densities with alveolar infiltration and a bronchial airway pattern. (b) Axial section revealing left pleural effusion with infiltration and an increased cardiothoracic index. (c) Axial section showing bilateral pleural effusions with multiple diaphragmatic appearances and (d) axial section at the pulmonary bases revealing multiple nodular densities and a clear density above the right diaphragm consistent with basilar pneumonia.

Figure 7.

Scrotal ultrasonography identified a right inguinal hernia without signs of incarceration, a right-sided hydrocele with a diameter of 82 mm with anechoic contents, and significant soft tissue edema involving bilateral inguinal regions and scrotal walls, more pronounced on the right side.

Audiological examination and primary diagnosis

Formal audiological assessment could not be completed due to patient noncooperation; however, clinical history revealed progressive bilateral sensorineural hearing loss. The clinical presentation, including primary hypogonadism, hypertrichosis, cutaneous hyperpigmentation, hallux valgus, documented hearing impairment, hematological abnormalities, hepatosplenomegaly, short stature, and genitourinary abnormalities, collectively suggested HS. Although genetic testing for mutations in the SLC29A3 gene was recommended, it was not performed owing to financial constraints of the patient’s family, limited resources, and the unavailability of an appropriate testing facility.

Treatments

Initial management focused on respiratory stabilization with supplemental oxygen therapy, resulting in improved oxygenation. Empirical antimicrobial therapy with intravenous ceftriaxone (1 g twice daily) and levofloxacin (500 mg once daily) was administered for 10 days to treat community-acquired pneumonia with suspected atypical pathogen involvement. Multidisciplinary consultations were performed, involving the urology team for urinary tract infection management and the general surgery team for elective inguinal hernia repair planning. Supportive care included fluid management, cardiac monitoring, and symptomatic treatment of associated conditions.

Outcome and follow-up

The patient demonstrated a favorable clinical response to treatment, with resolution of respiratory symptoms, improved oxygenation, and normalization of inflammatory markers. He was discharged on post-admission day 3 following clinical stabilization. Outpatient follow-up was scheduled for elective inguinal hernia repair, ongoing endocrine management, and multidisciplinary HS care coordination.

Discussion

HS was first comprehensively described by Molho-Pessach et al. in 2008, who reported the clinical phenotype in 10 individuals from 6 consanguineous Arab families. ⁵ To date, more than 130 cases have been reported worldwide, with a notable predominance among individuals of Arab descent, particularly Arab–Palestinians. ³ This geographic and ethnic clustering reflects consanguineous marriage patterns common among affected populations.

HS is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the SLC29A3 gene,^7,8 which encodes the human equilibrative nucleoside transporter-3 (hENT3) protein responsible for nucleoside transport. The hENT3 protein, composed of 475 amino acids, is predominantly localized to endosomes, lysosomes, and mitochondria. It mediates sodium-independent passive transport of nucleotides, nucleobases, and nucleotide analogs across intracellular membranes, thereby maintaining the cytoplasmic nucleoside pool essential for cellular metabolic processes. ⁸ Mutations in SLC29A3 impair nucleoside transport function, leading to disrupted cellular nucleoside homeostasis and consequent pathological manifestations characteristic of HS. ⁹ HS results from diverse SLC29A3 mutations, including missense, nonsense, frameshift, and deletion variants, which contribute to the considerable phenotypic variability observed among affected families. ¹⁰ Multiple pathogenic variants have been identified in the SLC29A3 gene, with certain mutations showing population-specific distributions. ¹¹ For instance, the c.1087 > T (p.R363W) mutation has been reported in Hispanic patients with HS, both of whom were homozygous for this mutation.^12,13 In addition, two patients with HS from the United States were found to be heterozygous for the c.1309G > A (p.G437R) mutation, which is among the most common mutations reported in individuals of Arab descent. ⁴ Therefore, these mutations serve as definitive diagnostic markers for HS, facilitating its differentiation from other syndromes with similar clinical manifestations.

The phenotypic heterogeneity of HS often results in diagnostic challenges and potential misdiagnosis. ³ The most common clinical manifestations, in descending order of occurrence, include hyperpigmented skin lesions (91%), hypertrichosis (68%) on the lower body (thighs, shins, and lower part of the abdomen and back), flexion contractures of the fingers (56%), sensorineural hearing loss (53%), short stature (49%), hepatosplenomegaly (40%), and hallux valgus (25%).^3,11,14,15 Short stature in patients with HS is often associated with low levels of growth hormone and insulin-like growth factor-1 (IGF-1). ¹ Recurrent fever and joint inflammation have been reported in some cases, with laboratory tests frequently revealing chronic elevation of inflammatory markers. ⁴ Consistent with these clinical descriptions, our patient exhibited many typical manifestations reported in the literature. Notably, although the upper body (including the arms and chest) was predominantly affected in the present case, the disease progression originated from the inner thighs and extended in a cephalad direction. Hypogonadism, reported in 16% of HS cases, represents another endocrine manifestation. However, comprehensive evaluations remain limited, with some patients exhibiting hypogonadotropic characteristics and others demonstrating hypergonadotropic features. ¹⁴ Male patients may present with scrotal masses, gynecomastia, and azoospermia. ¹ Additionally, affected males may present with micropenis. Chronic diarrhea, typically resulting from pancreatic exocrine dysfunction, has also been reported. ⁴ In the present case, basal and stimulated gonadotropin levels were consistent with hypogonadotropic hypogonadism, which manifested as absent secondary sexual characteristics. Moreover, HS is associated with various hematologic abnormalities, including severe anemia with reticulocytopenia, pancytopenia, red cell aplasia, and myelofibrosis. ² Our patient presented with moderate anemia. Although not observed in our patient, IDDM may occasionally represent the sole manifestation of HS in some cases. Other notable clinical features include complete agenesis of the inferior vena cava with associated varicose veins and proptosis. ² A rare complication observed in our case was severe tricuspid valve regurgitation with associated pulmonary hypertension. Previous studies have documented a broad spectrum of cardiac manifestations in HS, including mild pulmonary stenosis, pericardial effusion, pulmonary hypertension, patent ductus arteriosus with right-to-left shunt, septal defects, mitral valve prolapse, cardiomegaly, and myocardial hypertrophy. ¹⁶

A diagnosis of HS is often suggested by its distinctive cutaneous features; in their absence, a combination of additional clinical findings may raise suspicion. ¹⁷ Histological examination of skin lesions typically reveals a perivascular infiltrate in the dermis and subcutis, predominantly composed of histiocytes and plasma cells, which may progress to fibrosis. ¹⁶ A definitive diagnosis is established via genetic screening for SLC29A3 mutations. ¹⁷ However, HS diagnosis is challenging due to a broad differential diagnoses that include scleroderma, morphea, and arthritis, particularly because some patients may test positive for antinuclear antibody.^1,6 Consequently, genetic testing not only confirms the diagnosis but also enhances the understanding of the pathophysiological mechanisms underlying the syndrome and provides clinicians with essential information regarding prognosis and potential complications.

The complex pathophysiology of HS has led to the use of diverse treatment modalities, including corticosteroids and nonsteroidal anti-inflammatory drugs as well as several immunosuppressive agents, such as cyclosporine, methotrexate, cyclophosphamide, 6-mercaptopurine, and adalimumab; however, these treatments have demonstrated limited efficacy. Tocilizumab has demonstrated effectiveness in managing arthritis and short stature as well as in increasing IGF-1 levels. ⁶ Mycophenolate mofetil has also shown promise in the treatment of this syndrome.^2,6 Overall, most therapeutic interventions have been unsuccessful, with the exception of hypertrichosis, which may respond to laser therapy. Some symptoms, such as hearing loss and short stature, can be addressed independently. ⁶ Patients with HS are frequently misdiagnosed with dermatologic or rheumatologic conditions before the correct diagnosis is established. The first manifestations of this syndrome typically appear during the first or second decade of life, making early diagnosis essential for implementing effective preventive and therapeutic strategies. ¹⁷ Early diagnosis is therefore crucial for optimizing preventive and therapeutic interventions in affected individuals.

Conclusion

HS is an extremely rare condition, with only one case reported from Syria to date, further underscoring its rarity. The prominent endocrine features of HS warrant evaluation of this condition in patients presenting with hypogonadism, micropenis, gynecomastia, or short stature, particularly when accompanied by cutaneous hyperpigmentation, hypertrichosis, or hearing loss. Greater awareness among rheumatologists and dermatologists is crucial to avoid diagnostic and treatment delays. The prevalence of HS in low-income populations with high consanguinity highlights the importance of developing affordable methods for mutation analysis.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251394828 - Supplemental material for A rare case of H syndrome with severe multisystem involvement: Clinical challenges in low-resource healthcare settings

Supplemental material, sj-pdf-1-imr-10.1177_03000605251394828 for A rare case of H syndrome with severe multisystem involvement: Clinical challenges in low-resource healthcare settings by Ayham Qatza, Abdullah Dukhan, Mohammad Almoustafa, Ahmed Sheikh Sobeh, Abdullah Al wattar and Thaer Douri in Journal of International Medical Research