The H syndrome – Understanding Y

By Warren R. Heymann, MD
April 15, 2020
Vol. 2, No. 15

It has been more than a decade since the H syndrome was described by Molho-Pessach et al, in their report of 10 patients from 6 Arab consanguineous families. (1) More than 100 cases have now been reported worldwide. Because of its panoply of findings, it may be underrecognized.

Dermatology is replete with acronyms — I cannot think of another syndrome known by one letter, but you will now understand why this is the case. H syndrome (OMIM # 602782) is characterized by the cutaneous features of Hyperpigmentation, Hypertrichosis, and induration. Specific systemic manifestations associated include Hearing loss, Heart anomalies, Hepatomegaly, Hypogonadism, Hyperglycemia (diabetic mellitus), low Height (short stature), Hallux valgus (flexion contractures), and Hematological abnormalities. (2) The phenotypic spectrum is Huge.

H syndrome usually presents in the first or second decade of life. (3) Dermatologists should consider the diagnosis of H syndrome by recognizing its hallmark features, notably the presence of bilateral, symmetrical hyperpigmented indurated patches with overlying hypertrichosis, predominantly involving the medial aspects of the thighs. A recent report noted premature canities (4) and a case has been described with an adult onset of cutaneous manifestations only. (5) Histopathology demonstrates widespread fibrosis and thickened collagen bundles. (4) Histiocytes may be CD68 (+), S100 (+), and CD1a(-), and demonstrate emperipolesis, as appreciated in Rosai-Dorfman disease. (6)

The main differential diagnostic considerations are two syndromes: POEMS (which is not known to be genetic) and Winchester Syndrome (WS). POEMS syndrome is defined by Polyneuropathy, Organomegaly, Endocrinopathies, M protein, and Skin changes (hyperpigmentation, hypertrichosis, hyperhidrosis, sclerodermoid thickening, and angiomas). The lack of paraproteinemia and neurologic symptoms and early age of onset, combined with consanguinity of the parents, favor a diagnosis of H syndrome. WS may also present with thick skin, hyperpigmentation, and hypertrichosis, but these findings are not restricted to the lower half of the body as they are with the H syndrome. (1). The other key findings in WS are skeletal defects characterized by destruction and resorption of the affected bones with consequent skeletal deformities and functional impairment. (7).WS is an autosomal recessive disorder due to homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14). (8)

The H syndrome is an autosomal recessive disorder caused by bi-allelic mutations in the SLC29A3 gene, that encodes ENT3 (equilibrative nucleoside transporter 3), a nucleoside transporter protein. The ENT3 protein is found in intracellular membranes, especially in lysosomal and mitochondrial membranes. Because of the vast biochemical roles of nucleoside molecules, any disruption in metabolism and trafficking of nucleosides could result in various abnormal phenotypes. (9) The H syndrome is considered a histiocytic disorder (histiocyosis lymphadenopathy pus syndrome). (10) Other histiocytic maladies described in the literature such as familial Rosai-Dorfman (Faisalabad histiocytosis), and pigmented histiocytosis with insulin-dependent diabetes, are now suspected to be part of a spectrum of disorders involving mutations of SLC29A3. (5)

According to Low et al, “Treatments reported in the literature included systemic corticosteroids, methotrexate, cyclophosphamide, cyclosporine, 6‐mercaptopurine, interferon‐alpha, colchicine, anakinra, canakinumab, adalimumab, nonsteroidal anti‐inflammatory drugs, tocilizumab, and radiotherapy. These treatment regimens nevertheless were either ineffective or only resulted in partial responses.” (11)

The most important role dermatologists have in H syndrome is recognizing the pathognomonic cutaneous features of the disease and referring patients to our colleagues in genetics and other appropriate subspecialties. On a broader scale, I am perpetually awestruck as to how genetic evaluation by whole exome (or genome) sequencing can precisely define the mutation(s) of syndromes that were previously considered disparate and distinct. Alphabetically, knowing the Y of H gets an A.

Point to Remember: The H syndrome should be considered by dermatologists in younger patients presenting with hyperpigmented, hypertrichotic, and indurated lesions of the legs.

Our Expert’s Viewpoint

Jennifer L. Hand, MD
Associate Professor of Dermatology, Genetics, and Pediatrics
Mayo Clinic, Rochester, Minnesota

Genetic testing has become big business and transformed the options to evaluate rare disorders. In choosing genetic tests, clinicians must balance between “shoot for the moon” and reality. For the rarest, unknown disorders, whole exome sequencing (WES) is the top of the line. Whole sequence testing is still considered too expensive and impractical for clinical use. WES, however, offers power because most relevant mutations are found in the exons, that is, the expressed areas of DNA. If a patient’s disorder is more common, a simpler targeted test for relevant genes is still best, because unlike WES, targeted testing examines both introns and exons. With no answer by targeted testing, or for genetic disorders of unknown cause, WES just might provide the key. I always refer patients for professional genetics consultation before genetic testing. The real work for these tests is interpreting the results, arranging insurance coverage, and understanding the potential implication for the whole family. This requires patient support before and after testing which I find works better with help from a genetics team. Patients can find genetics services locally by using the American College of Medical Genetics and Genomics website, and searching by ZIP code or city.

1. Molho-Pessach V, Agha Z, Aamar S, Glaser B, et al. The H syndrome: A genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. J Am Acad Dermatol 2008; 59: 79-85.

2. Yesudian P, Sarveswari KN, Karrunya KJ, Thomas K. H syndrome - A case report. Indian Dermatol Online J 2019; 10: 300-302.

3. Molho-Pessach V, Lerer I, Abelovich D, Agha Z, et al. The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am J Hum Genet 2008; 83: 529-534.

4. Al-Hamadi KI, Ismael DK Saadoon AQ. H syndrome with possible new phenotypes. JAAD Case Rep 2019; 5: 355-357.

5. Wang X, Sun J. Skin-limited H syndrome in a Chinese man. Australas J Dermatol 2019; 60: 243-245.

6. Molho-Pessach V, Ramot Y, Camille F, Doviner V, et al. H Syndrome: The first 79 patients. J Acad Dermatol 2014;70: 80-88.

7. Grover S, Grewal RS, Verma R, Mani R, et al. Winchester syndrome: A case report. Int J Dermatol 2009; 48: 145-147.

8. Evans BR, Mosig RA, Lobl M, Martignetti CR, et al. Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. Am J Hum Genet 2012; 91: 572-576.

9. Noavar S, Behroozi S, Tatarcheh T, Parvini F, et al. A novel homozygous frame-shift mutation in the SLC29A3 gene: A new case report and review of the literature. BMC Med Genet 2019; 20: 147.

10. Bhatti S, Jamil A, Siddiqui SH, Yaqoob U, et al. The H syndrome: A genodermatosis Cureus. 2018; 10(6): e2763.

11. Low DE, Tang MM, Surana JY, Pramano ZAD, Leong KF. H syndrome – the first report in Malaysia. Int J Dermatol 2019 Jun 13 [Epub ahead of print]