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Received date: 19/12/2024 Published date: 20/12/2024 Case Report

H Syndrome: A Case Series of 3 Patients was First Described in Syria and a Literature Review

Sajeda Alnabelsi*, Hussein Abdallah, Nemat Alsaghir, Kinda Alshawa

Damascus University, faculty of medicine, Hospital of Dermatology and Venerology, Damascus, Syria

*Corresponding author

*Sajeda Alnabelsi, Damascus University, faculty of medicine, Hospital of Dermatology and Venerology, Damascus, Syria.

DOI: 10.55920/JCRMHS.2024.08.001364

Introduction

Monogenic auto-inflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome without evidence of autoimmunity. The mutated proteins are involved in the altered regulation of inflammation (1). The H syndrome has been recently described as a rare monogenic auto-inflammatory autosomal recessive histiocytosis, with a prevalence of less than 1 in 1,000,000. It is characterized by typical cutaneous findings and associated systemic manifestations(2).It is caused by mutations in the solute carrier family 29 (SLC29A3) gene, which encodes the human equilibrative nucleoside transporter-3(hENT3), a protein found in endosomes, lysosomes, and mitochondria(3).It was first described by Molho-Pessach et al in 2008, also naming it H syndrome considering the fact most of the clinical features start with the letter “H” (4) and the first described cases were from Arab descendant (7) .Thereafter, about 100 patients of H syndrome have been described worldwide(5). H syndrome is now considered to include pigmented hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis (FHC), and familial sinus histiocytosis with massive lymphadenopathy (FSHML).(2). Symmetrical cutaneous hyperpigmentation involving inner thighs accompanied by hypertrichosis and sclerodermatous induration are the most common features observed and considered hallmark of the disease.

Case presentation

Patient 1: A 15-year-old male presented with asymptomatic bilateral hyper-pigmented patches on the lower limbs, his medical history reveals congenital glaucoma and delayed puberty. On examination: short stature (152cm), stiffness dark brown well demarcated patches on lower limbs, exophthalmos and dilated scleral vessels, flexion contractures in some fingers. Lab tests were within normal except (HGB: 10g/dl, AST: 150U/L, ALT: 187U/L, testosterone: 100ng/dl, HbA1c: 9.3%).

Patient 2: A 15-year-old female presented with bilateral hyper-pigmented plaques on thighs and shines, her medical history reveals bilateral hearing loss, amenorrhea, tingling in the fingertips, excessive thirst and urination and the familial history shows bilateral hearing loss diagnosed in her brother. On examination: bilateral pigmented well demarcated patches on thighs and shins, exophthalmos, bilateral inguinal lymphadenopathy and erythema. Lab tests were within normal except (glucose: 458mg/dl, Esr: 60mm/hr, HbA1c: 17%, LH/FSH: 17). Axillary echography shows multiple masses exceed 1cm in diameter, inguinal echography shows bilateral oedema in subcutaneous tissue.

Patient 3: A 16-year-old female presented with hyper-pigmented patches on thighs and genitalia, her medical history reveals moderate hearing loss, heart disorders, primary amenorrhea, IDDM. On examination: short stature (130cm), stiffness hyperpigmented well demarcated patches on genitalia and thighs, spleenomegaly, flexion contractures in two fingers and 4 toes. Lab tests were within normal except: (HGB: 7.4g/dl, MCV: 70fl, glucose: 320mg/dl, ESR: 123mm/hr, GH: 0.05ng/ml). peripheral blood smear showed microcytic hypochromic anemia, abdominal echography showed enlargement in spleen 3cm below costal margin. the cardiologist consultation showed systolic murmur in aortic valve area, echocardiography showed: tricuspid and mitral regurgitation, secondary ASD measures 1.2cm.

Figure 1: Patient no 1
(A).Plaques of hyperpigmentation and hypertrichosis on the thighs.
(B). Hyperpigmentation on the legs
(C). Flexion contractures in the last 3 fingers
(D). Scleral vessels dilation

Figure 2:
(A, B, C). Hyperpigmentation in the inner sides of the thighs and legs.
(D). Flexion contractures in the fingers
(E). exophthalmos.
(F). in the top: inguinal echography shows edema in subcutaneous tissue. (the red line) In the bottom: Axillary echography shows multiple masses exceeding 1cm in diameter. (The red circle)

Figure 3:
(A, B). plaques of Hyperpigmentation and hypertrichosis on the inner sides of the thighs and the genitalia and buttock.
(C, D). flexion contracture in fingers and toes.
(E). hyperkeratosis, acanthosis, and increased melanin deposition in basal keratinocytes (H&E, x10).
(F). interstitial inflammatory infiltrate (H&E, x10).
(G). mix of histiocytes, dendrocytes, plasma cells, lymphocytes, and mast cells in the dermal infiltration (H&E, x40)

Discussion

H syndrome, also known as Hermansky-Pudlak syndrome type 9 (HPS9), is a rare, multisystem, autoinflammatory disorder mainly affecting patients of Arab and, less commonly, Indian descent (7). It was first described by Molho-Pessach et al in 2008, also naming it H syndrome considering the fact most of the clinical features start with the letter “H”: Hyperpigmentation, Hypertrichosis, Hepatosplenomegaly, Hearing loss, Hypogonadism, Hyperglycemia, Hallux valgus, Histiocytosis, Heart anomaly, Hypertelorism, Hypothyroidism. The lesions start to appear mainly in the first or second decade of life (6).

H syndrome is part of the histiocytosis-lymphadenopathy plus syndrome, which includes three other histiocytic disorders once thought to be separate entities:
●Faisalabad histiocytosis (FHC).
● Familial sinus histiocytosis with massive lymphadenopathy (familial Rosai-Dorfman disease)(FSHML).
●Pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID).

This group of diseases is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene on chromosome 10q22, encoding the solute carrier family 29 member 3, also called the equilibrative nucleoside transporter 3, which mediates the uptake of precursors for nucleotide synthesis by salvage pathways.

The clinical manifestations of H syndrome are widely variable. Its hallmark is cutaneous hyperpigmentation, which becomes apparent during childhood and is associated with sclerodermatous skin induration and hypertrichosis (4). The hyperpigmented and hypertrichotic plaques are located in the middle and lower parts of the body, and these manifestations were the main findings in our case series. Extracutaneous manifestations may include sensorineural hearing loss, hepatosplenomegaly, short stature, cardiac anomalies (atrial septal defect, ventricular septal defect, mitral valve prolapse, and cardiomegaly), varicose veins, dilated lateral scleral vessels, facial telangiectasias, hallux valgus and fixed flexion contractures of fingers and toes, scrotal masses, and gynecomastia. Membranous nephropathy has been reported in one family (9). Chart (1)

Laboratory abnormalities include mild microcytic anemia, elevated erythrocyte sedimentation rate, elevated liver enzymes, growth hormone deficiency, high gonadotropin levels, and low to normal testosterone levels. A biopsy of the involved skin shows hyperkeratosis, acanthosis, and increased melanin deposition in basal keratinocytes; widespread fibrosis of the dermis and subcutis; and an interstitial inflammatory infiltrate composed of small to medium-sized histiocytes, dendrocytes, plasma cells, lymphocytes, and mast cells (10). The same findings were seen in biopsies from enlarged lymph nodes and from nasal mucosa biopsies. (5,7)

The diagnosis of H syndrome is suspected based on the clinical findings. Mutational analysis will confirm the diagnosis when there is uncertainty or in patients with mild or incomplete phenotypes, mainly by WES (Whole Exome Sequencing) and Sanger sequencing for scientific purposes and screening in families. However, no genetic tests were performed for any patient because they aren’t available in Syria.

H syndrome does not have any standard treatment for preventive and therapeutic approaches toward its cutaneous and systemic presentations apart from hypertrichosis that could be almost permanently removed by laser. However, the latest findings suggest that there is a possibility of prevention of short stature or other cutaneous and systemic complications in this syndrome with earlier diagnosis and treatment. There is no established treatment for H syndrome. Therapies that have been attempted include systemic corticosteroids, immunosuppressive agents, interferon-alpha, adalimumab, and radiotherapy (4).

Conclusion

H syndrome is an extremely rarely reported entity more so in the Indian and Arab world, and presents mainly with dermatologic manifestations. We present this case series to increase the awareness of this entity

References

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