H syndrome is a rare autosomal recessive genodermatosis caused by mutations in the SLC29A3 gene, which encodes the human equilibrative nucleoside transporter 3 (hENT3). The syndrome was first characterized in 2008 by Molho-Pessach et al. [1] who coined the name “H syndrome” due to the predominance of clinical manifestations beginning with the letter H—including hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, and hyperglycemia. Subsequent work by Molho-Pessach and colleagues confirmed that pathogenic variants in SLC29A3 are responsible for this disorder [2]. Approximately 100 cases have been reported worldwide, with the majority documented in Middle Eastern populations—particularly among individuals of Arab descent [3]. H syndrome is now considered a novel form of histiocytosis, characterized by systemic inflammatory accumulation of histiocytes with a distinctive immunophenotype [4,5]. The cutaneous findings—symmetrical, indurated, hyperpigmented plaques with overlying hypertrichosis—are considered pathognomonic and often serve as the first clue for recognition [3,4]. Because the disorder shares features with various inflammatory, metabolic, and histiocytic diseases, delayed or incorrect diagnosis is common. Early recognition is essential to guide systemic evaluation, avoid unnecessary treatments, and provide appropriate genetic counseling.

The patient was an 11-year-old male born to non-complicated pregnancy in Kirkuk, Iraq, delivered at term by spontaneous vaginal delivery. His birth weight was 2.6 kg, consistent with small for gestational age, although early growth and developmental milestones were normal. At approximately one year of age, his parents observed progressive hyperpigmentation over the lower limbs along with emerging joint deformities. These manifestations gradually worsened over the following years, and he was initially diagnosed with systemic-onset juvenile idiopathic arthritis.

By the age of 11, the child presented with a nine-year history of symmetrical hyperpigmented, indurated plaques over the medial thighs and legs, accompanied by pronounced hypertrichosis of the lower limbs and both cheeks. He had significant swelling of both knees, ankles, and feet, along with persistent arthralgia. The parents also reported a five-year progression of severe bilateral sensorineural hearing loss, confirmed on audiological studies, and he had developed noticeable slurred speech.

Physical examination revealed pallor, mild splenomegaly, and marked short stature, with height measuring 127 cm and weight 28 kg, both below the 3rd percentile for age. The genital examination showed normal testes but a micropenis, and musculoskeletal assessment identified bilateral hallux valgus. Ophthalmologic evaluation detected bilateral retinopathy. No family history of similar skin or systemic diseases was reported. Laboratory investigations demonstrated microcytic iron-deficiency anemia with hemoglobin of 9.7 g/dL, elevated ESR (75 mm/hr) and CRP (48 mg/L), while white blood cell count, platelets, liver and renal function tests, thyroid profile, blood glucose, HbA1c, lipid profile, electrolytes, and CPK were within normal limits. Autoimmune markers, including ANA, anti-dsDNA, and rheumatoid factor, were negative. Viral hepatitis screening was also normal. Ultrasound of the abdomen revealed mild splenomegaly, while scrotal and neck ultrasonography and echocardiography were unremarkable. A chest radiograph showed no abnormalities (Figure 1-4).

A skin biopsy obtained from the hyperpigmented plaque demonstrated irregular acanthosis, increased basal layer melanin, significant thickening of dermal collagen bundles, and dense perivascular inflammatory infiltrates composed mainly of histiocytes and lymphocytes. An increased number of hair follicles and pilosebaceous units were seen, consistent with the clinical suspicion of H syndrome.

Whole-exome sequencing (WES) confirmed a pathogenic mutation in the SLC29A3 gene, establishing the diagnosis.

H syndrome represents a multisystemic inflammatory disorder with characteristic clinical and histopathologic features. The symmetrical hyperpigmented, indurated plaques with dense hypertrichosis observed in our patient align with previously described hallmark manifestations [1,3,4]. These cutaneous features are often the key to distinguishing H syndrome from other conditions, including systemic sclerosis, morphea, and metabolic disorders. The disorder stems from SLC29A3 mutations, resulting in loss of function of hENT3, which disrupts intracellular nucleoside transport and leads to dysregulated histiocytic activation [2]. This pathogenic mechanism explains the overlap between H syndrome and other SLC29A3-associated disorders, including familial Rosai–Dorfman disease, Faisalabad histiocytosis, and PHID syndrome (pigmented hypertrichosis with insulin-dependent diabetes) [5–7]. Our patient demonstrated multiple systemic features consistent with published literature, including short stature, hallux valgus, arthropathy, hearing loss, and mild splenomegaly, all of which have been previously reported among classical manifestations of the syndrome [3,4,8]. Severe sensorineural hearing loss, as in our case, represents one of the most frequently documented neurological findings [1,3]. While cardiac involvement—particularly pericardial disease—is common, it was absent in this patient, consistent with the variability in systemic expression [3,8]. Similarly, though insulin-dependent diabetes mellitus may present as an early or isolated manifestation [6], glucose metabolism remained normal. Hematologic abnormalities such as anemia, pancytopenia, red cell aplasia, and myelofibrosis have been reported, reflecting the histiocytic nature of the disease [5]. Our patient exhibited microcytic anemia without evidence of bone marrow suppression. Rare complications, including pancreatic exocrine insufficiency [7], agenesis of the inferior vena cava [8], and proptosis or exophthalmos [9], have been described, highlighting the extensive phenotypic variability. The main differential diagnosis includes Rosai–Dorfman disease (RDD), given shared histopathologic features such as S100-positive histiocytes and emperipolesis [5]. However, the distinctive distribution of hyperpigmented, hypertrichotic plaques and systemic features unique to H syndrome allow differentiation [1,3]. No curative therapy exists. Management focuses on symptom control, particularly for systemic inflammation, hearing impairment, endocrine abnormalities, and orthopedic deformities. Emerging evidence indicates that biologics—especially IL-6 inhibitors—may provide partial benefit in selected cases [12]. Ultimately, genetic confirmation is essential for diagnosis and family counseling. As consanguinity remains common in many Middle Eastern regions, awareness of H syndrome is crucial to prevent misdiagnosis and unnecessary interventions. To our knowledge, this represents the first genetically confirmed case from Iraq, filling an important gap in regional dermatogenetic literature.

Figure 1: A hallux valgus deformity of both feet, B bilateral knee joint swelling and leg hypertrichosis, C cheek hyperpigmentation and large ears, D lower back hyperpigmentation, E bilateral inner thigh and genital hyperpigmentation with small penis, F abdominal distention and promenance ribs

Figure 2: Camptodactily in both hands and feet

Figure 3: A whole exome sequence supporting the diagnosis of H syndrome

Figure 4: Hyperpigmentation and hypertrichosis

H syndrome is an exceptionally rare autoinflammatory genodermatosis, and this report represents the first documented case from Iraq. The presence of symmetrical hyperpigmented, hypertrichotic plaques in combination with short stature, hearing loss, and systemic inflammation should prompt clinicians to consider this diagnosis. Increased awareness and prompt genetic testing are essential for early diagnosis, optimal management, and appropriate family counseling.

1. Molho-Pessach, Vered, et al. “The H Syndrome: A Genodermatosis Characterized by Indurated, Hyperpigmented, and Hypertrichotic Skin with Systemic Manifestations.” Journal of the American Academy of Dermatology, vol. 59, no. 1, 2008, pp. 79–85. https://doi.org/10.1016/j.jaad.2008.03.021

2. Molho-Pessach, Vered, et al. “The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3.” American Journal of Human Genetics, vol. 83, no. 4, 2008, pp. 529–534. https://doi.org/10.1016/j.ajhg.2008.09.013

3. Molho-Pessach, Vered, et al. “H Syndrome: The First 79 Patients.” Journal of the American Academy of Dermatology, vol. 70, no. 1, 2014, pp. 80–88. https://doi.org/10.1016/j.jaad.2013.09.019

4. Tekin, Betül, et al. “H Syndrome: A Multifaceted Histiocytic Disorder with Hyperpigmentation and Hypertrichosis.” Acta Dermato-Venereologica, vol. 95, no. 8, 2015, pp. 1021–1023. https://doi.org/10.2340/00015555-2145

5. Avitan-Hersh, Etty, et al. “A Case of H Syndrome Showing Immunophenotype Similarities to Rosai–Dorfman Disease.” American Journal of Dermatopathology, vol. 33, no. 1, 2011, pp. 47–51. https://doi.org/10.1097/DAD.0b013e3181ee547c

6. Broshtilova, Violeta, et al. “Diabetes Mellitus May Be the Earliest and Sole Manifestation of the H Syndrome.” Diabetic Medicine, vol. 26, no. 12, 2009, pp. 1179–1180. https://doi.org/10.1111/j.1464-5491.2009.02843.x

7. Hussain, Khalid, et al. “Diabetes Mellitus, Exocrine Pancreatic Deficiency, Hypertrichosis, Hyperpigmentation, and Chronic Inflammation: Confirmation of a Syndrome.” Pediatric Diabetes, vol. 10, no. 3, 2009, pp. 193–197. https://doi.org/10.1111/j.1399-5448.2008.00470.x

8. Mutlu, Gül Y., et al. “Agenesis of the Inferior Vena Cava in H Syndrome Due to a Novel SLC29A3 Mutation.” Pediatric Dermatology, vol. 30, no. 1, 2013, pp. e70–e73. https://doi.org/10.1111/pde.12085

9. Molho-Pessach, Vered, et al. “Ophthalmologic Findings in H Syndrome: A Unique Diagnostic Clue.” Ophthalmic Genetics, vol. 36, no. 4, 2015, pp. 365–368. https://doi.org/10.3109/13816810.2014.886272

10. Mehta, Swati, et al. “The H Syndrome.” Indian Journal of Paediatric Dermatology, vol. 16, no. 2, 2015, pp. 102–104.

11. Kemal, Yasemin, et al. “H Syndrome Presenting with Recurrent Fever, Arthritis, and Systemic Inflammation.” Clinical Rheumatology, vol. 37, no. 5, 2018, pp. 1381–1386. https://doi.org/10.1007/s10067-017-3948-y

12. Gupta, L., et al. “H Syndrome: Expanding the Clinical Spectrum and Therapeutic Experience.” Pediatric Rheumatology, vol. 15, no. 1, 2017, p. 47. https://doi.org/10.1186/s12969-017-0204-y