Background familial sinus histiocytosis with massive lymphadenopathy (FSHML).

Background  H syndrome is a rare systemic inheritedhistiocytosis, with a prevalence of less than 1 /1000000.

It is characterisedby typical cutaneous findings and associated systemic manifestations. The majorclinical findings are hyperpigmentation, hypertrichosis, hepatosplenomegaly,heart anomalies and hearing loss. The major commonendocrine manifestations include hypogonadism, short stature and diabetesmellitus.Due to overlappingclinical features, H syndrome is now considered to include pigmentedhypertrichosis with insulin dependent diabetes mellitus syndrome (PHID),Faisalabad histiocytosis (FHC) and familial sinus histiocytosis with massivelymphadenopathy (FSHML). Here, we report 2 cases of  H-syndrome, both in paediatric age group andboth of which were proven using genetic testing.Discussion and Conclusion            H syndrome is a rare autosomal-recessive histiocytosis with characteristic cutaneous findings andaccompanying systemic manifestations systemic manifestations. The majorclinical and laboratory findings of hyperpigmentation and hypertrichosis, hepatosplenomegaly,heart anomalies, hearing loss, hypogonadism, low height, and occasionally,hyperglycemia1. A few patients have been reported from India 2,3.

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Males have been reported to have scrotal masses, gynecomastia, andazoospermia 2, as seen in one of our case. Previous case reportshave revealed that testicular ultrasound examination showed echogenicthickening of both the spermatic cords and the scrotal sac, with normal-sizedtestes1. Other features that are described are varicose veins,hallux valgus, fixed flexion contractures of interphalangeal joints. Thecommonest among them are hyperpigmentation, phalangeal flexion contractures,hearing loss, and short stature, seen in around 40% subjects. Insulin-dependentdiabetes mellitus and lymphadenopathy are found in around 20% of these patients3.These patients develop progressive cutaneous hyperpigmented, hypertrichotic,and indurated plaques over the lower limbs and lower abdomen during the firstor second decade of life, which is the hallmark for the diagnosis. However asmentioned earlier in the case 1 this hallmark cutaneous pigmentation may besubtle especially in patients with a darker skin complexion and may be missedon a cursory physical examination. The waxing and waning of cutaneousmanifestation also hinders timely diagnosis.

 The table belowshows the major clinical features in H syndrome that has been described andtheir presence in our two patients.      Clinical features Case 1 Case 2 Origin Lakshadweep Indian Sex Female Male Age at presentation 9 9 Location of cutaneus manifestation Thigh Thigh Genital masses – + Micropenis – – Gynecomastia – – Varicose veins – – Hepatosplenomegaly – – Short Stature + + Hypogonadism – – Episcleritis /exophthalmos – – Facial telengiectasia – – Flexion contracture – – Mental retardation – – IDDM + + Malabsorption – – Flat foot / hallux valgus – – Sensori neural hearing loss + + Lympadenopathy – – Hematologic – –  Laboratory testswill show an elevated erythrocyte sedimentation rate and CRP , mild microcyticanemia, and elevated liver enzymes. Though liver enzymes were normal in ourpatients, they had an elevated C Reactive protein and ESR.  Hypogonadism (hyper- or hypogonadotropic) andazoospremia may be observed. Histopathologic examination of the involved skinis characterized by inflammation, with seborrheic keratosis-like acanthosis inthe basal layer, histiocyte infiltration, and a perivascular mononuclearinfiltrate, with plasma cells and mast cells throughout the dermis andsubcutaneous fat1-3. These histiocytes are mainly CD-68 positive andsometimes S100 positive8.                                                Genetic analysis in our both patients revealed a reported homozygousmissense mutation, p.Arg134Cys, in the SLC29A3gene 2.

Mutations in the SLC29A3gene were initially described to present as 2 allelic disorders- one wasa  diabetes-type pigmented hypertrichosiswith insulin dependent diabetes mellitus and second as deafness-type H syndrome4,5.Butboth our cases had coexistant deafness and diabetes mellitus in addition to thetypical cutaneous manifestations. There are many other case series5,6  that has reported similar presentation,contrary to the concept of discrete allelic disorders. Mutations in the SLC29A3 gene have also been found in Rosai-Dorfmandisease and Faisalabad histiocytosis, which has also been reported to haveimmunophenotypic similarities such as positivity for CD68, CD34, and factorXIIIa7. Till date, around 20 different mutations have beenidentified in SLC29A3, with the majorityof them located in exon 62,3.But both the cases we have reported,had a mutant SLC29A3 located in exon 4. The reason for the variousmanifestations are still unclear but it might be probably because of hENT3mutations that alter nucleoside pool and decrease ATP in mitochondria andlysosomes perturbing their homeostatic functions9. The reason forshort stature and GH-IGF axis in this syndrome is yet to be explored.

                        Till date, we couldfind around 100 published cases of H syndrome ,around 80 of them with molecularconfirmation. This should be considered as a remarkable number for a relativelynovel autosomal recessive disorder, which implies that the disorder is not asrare as it is thought to be. Conclusion    Though it has been considered as a very rare disorder , we couldfind as many as 100 case reports till date for a relatively novel disorder.

This syndrome is often being misdiagnosed or even undiagnosed and henceunreported. The characteristic cutaneous manifestation along with genetictesting , is the key to diagnosis. However, the subtle skin pigmentation andits waxing and waning course delays timely diagnosis.

The hearing loss alsovaries in severity and can go unrecognised. It is possible that cases goundiagnosed or are not diagnosed properly because of its overlapping featureswith other syndromes. A timely diagnosis would however avoid unnecessaryinvestigations and help us look for the other components of this syndrome. 


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