Journal of Diabetology

: 2020  |  Volume : 11  |  Issue : 3  |  Page : 214--217

H syndrome presenting as juvenile diabetes: an underdiagnosed entity

Kingini Bhadran, Manjunath P. Ramakrishna, Nisha Bhavani, Praveen V Pavithran 
 Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

Correspondence Address:
Dr. Praveen V Pavithran
Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala.


H syndrome is a rare recessively inherited histiocytosis resulting from mutations in the SLC29A3 gene which encodes the human equilibrative nucleoside transporter 3 (hENT3).This multisystem disorder can have myriad of presentations ,with skin lesions ,sensory hearing loss and insulin dependent diabetes being the most characteristic.The most important step in the correct diagnosis involves awareness about the entity and careful physical examination. Genetic analysis is essential to confirm the diagnosis as it has many shared clinical features with other histiocytosis, with systemic manifestations which may confuse the physician. Management is symptomatic depending on the clinical presentation.Here we describe two genetically proven patients with H syndrome in whom diagnosis was missed for several years.Both patients presented in their second decade with clinical features suggestive of H syndrome. Increasing awareness is contributing to more reporting and helps in avoiding unnecessary evaluation.

How to cite this article:
Bhadran K, Ramakrishna MP, Bhavani N, Pavithran PV. H syndrome presenting as juvenile diabetes: an underdiagnosed entity.J Diabetol 2020;11:214-217

How to cite this URL:
Bhadran K, Ramakrishna MP, Bhavani N, Pavithran PV. H syndrome presenting as juvenile diabetes: an underdiagnosed entity. J Diabetol [serial online] 2020 [cited 2020 Oct 23 ];11:214-217
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Full Text


H syndrome (OMIM 6027820) is a rare systemic inherited histiocytosis, with a prevalence of less than 1 in 1,000,000. It is characterized by typical cutaneous findings and associated systemic manifestations. The major clinical findings are hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, and hearing loss. Endocrine manifestations include hypogonadism, short stature, and diabetes mellitus. Owing to overlapping clinical features, 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).[1] Here, we report two genetically proven cases of H syndrome, presenting as insulin-dependent diabetes mellitus (IDDM).

 Case Report

Case 1

An 11-year-old girl was referred to diabetic clinic in our institution with a 2-year history of diabetes, which was mostly uncontrolled. She was noted to be short since first grade, and she had an unremarkable past history except fourth-degree consanguineous parentage.

Initial physical examination was noted to be normal except for the short stature (height, 118cm and weight, 18kg, both below third centile). Glutamate dehydrogenase antibodies (GAD Ab) and antibody to insulinoma-associated antigen (IA2 Ab) were negative. Laboratory evaluation also revealed elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Her glycemic control was poor, with glycated hemoglobin (HbA1c) of 9.4%. Abdominal ultrasound was normal. As per departmental policy, cost-effective screening for non-autoimmune forms of diabetes was done by a detailed ophthalmological and audiological examination, which revealed moderate sensorineural deafness, which was not clinically apparent. Turner’s syndrome with autoimmune diabetes and diabetes insipidus, diabetes mellitus, and optic atrophy (DIDMOAD) were considered. It was at this juncture that a previously overlooked subtle ill-defined, hyperpigmented patch on the inner aspect of both thighs and back with hypertrichosis was noticed [Figure 1]. This lead to consideration of H syndrome as a diagnostic possibility. Skin biopsy was taken from the hyperpigmented patch, which showed epidermis with anastomosing acanthosis and orthokeratotic compact hyperkeratosis. The dermis was thickened and fibrocollagenous, and showed hyalinized vessels with perivascular infiltrate of lymphocytes and histiocytes, which was consistent with the diagnosis of H syndrome.{Figure 1}

After the confirmation of a normal female karyotype, samples were forwarded to Exeter, UK, for genetic testing. Testing involved analysis of all the coding regions and exon/intron boundaries of the monogenic diabetes genes (GCK, HNF1A, HNF4A, HNF1B, NEUROD1, INS, INSR, KCNJ11, ABCC8, PDX1, CEL, PAX6, GATA6, TRMT10A, WFS1, ZFP57, PCBD1, LMNA, PPARG, PLIN1, POLD1, EIF2AK3, FOXP3, GATA4, GLIS3, IER3IP1, PTF1A, NEUROG3, RFX6, SLC2A2, SLC19A2, SLC29A3, STAT3, CISD2, WFS1, ZFP57), and the m.3243A>G MIDD mutation by targeted next-generation sequencing was performed, which detected a previously reported SLC29A3 missense mutation, p.Arg134Cys, at location exon 4, which was later confirmed by Sanger sequencing.

The curious aspect of this case is the waxing and waning course of the cutaneous lesions, which seems to alternately fade and become prominent over course of weeks, which has not been reported previously.

Case 2

A 12-year-old boy was referred to our center with a possible diagnosis of DIDMOAD. Born of nonconsanguineous parentage, developmental delay led to the diagnosis of sensorineural deafness. Three years before his referral, he was diagnosed to have diabetes, which was being managed with multiple subcutaneous doses of insulin. In our diabetic clinic, he was noticed to have short stature (height, 114cm with third centile). Physical examination revealed a well-defined, hyperpigmented patch on the inner aspect of both thighs and back with hypertrichosis and bilateral testicular swellings. Ophthalmological examination was normal. There was no lymphadenopathy or organomegaly. A clinical diagnosis of H syndrome was made.

Laboratory evaluation revealed elevated ESR. Abdominal ultrasound was normal. Scrotal ultrasonography (USG) revealed normal testes with thickened scrotal sac and spermatic cords.

Genetic analysis in Exeter revealed a mutation, which was identical to that in the first case (p.Arg134Cys, in the SLC29A3 gene at exon 4) [Figure 2]. The two patients were from widely separated geographical locations. However, in view of the known population migration between the two regions, a founder effect is highly probable (courtesy Prof. S. Ellard, Molecular Genetics Laboratory, Royal Devon and Exeter Hospital, Exeter, UK).{Figure 2}

Clinical features of both patients have been described in [Table 1].{Table 1}


H syndrome (OMIM 6027820) is a rare autosomal-recessive histiocytosis with characteristic cutaneous findings and accompanying systemic manifestations. The major clinical and laboratory findings are hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, and occasionally, hyperglycemia.[2] Few patients have been reported from India.[3],[4] Males have been reported to have scrotal masses, gynecomastia, and azoospermia,[3] as seen in one of our case. In previous reports, testicular ultrasound examination showed echogenic thickening of both the spermatic cords and the scrotal sac, with normal-sized testes.[2] Other features that are described are varicose veins, hallux valgus, and fixed flexion contractures of interphalangeal joints. The most common among them are hyperpigmentation, phalangeal flexion contractures, hearing loss, and short stature, seen in around 40% of subjects. IDDM and lymphadenopathy are found in around 20% of these patients.[4] These patients develop progressive cutaneous hyperpigmented, hypertrichotic, and indurated plaques over the lower limbs and lower abdomen during the first or second decade of life, which is the hallmark for the diagnosis [Figure 3]. However, as mentioned earlier in Case 1, this hallmark cutaneous pigmentation may be subtle, especially in patients with a darker skin complexion and may be missed on a cursory physical examination. The waxing and waning of cutaneous manifestation also hinders the timely diagnosis as observed in our first case{Figure 3}

Laboratory tests usually show an elevated ESR and CRP, mild microcytic anemia, and elevated liver enzymes. Though liver enzymes were normal in our patients, they had an elevated CRP and ESR. Hypogonadism (hyper- or hypogonadotropic) and azoospermia may be observed. Histopathologic examination of the involved skin is characterized by inflammation, with seborrheic keratosis-like acanthosis in the basal layer, histiocyte infiltration, and a perivascular mononuclear infiltrate, with plasma cells and mast cells throughout the dermis and subcutaneous fat.[2],[3],[4] These histiocytes are mainly CD-68 positive and sometimes S100 positive.[5]

Genetic analysis in both patients revealed a reported homozygous missense mutation, p.Arg134Cys, in the SLC29A3 gene,[3] which was the same as the mutation reported by Priya et al.[6] The SLC29A3 gene encodes human equilibrative nucleoside transporter 3 (hENT3), a member of a largely conserved group of solute carrier (SLC) transporters called the ENT or SLC29 family. Mutations in the SLC29A3 gene were initially described to present as two allelic disorders—one as a diabetes-type pigmented hypertrichosis with IDDM and second as deafness-type H syndrome.[7],[8] But both our cases had coexistent deafness and diabetes mellitus in addition to the typical cutaneous manifestations. There are many other case series[8],[9] that have reported similar presentation, contrary to the concept of discrete allelic disorders. Mutations in the SLC29A3 gene have also been found in Rosai–Dorfman disease and Faisalabad histiocytosis, which have also been reported to have immunophenotypic similarities such as positivity for CD68, CD34, and factor XIIIa.[10] Till date, around 20 different mutations have been identified in SLC29A3, with the majority of them located in exon 6. But both our reported cases had a mutant SLC29A3 located in exon 4. The reason for the various manifestations are still unclear but it might be probably because of hENT3 mutations that alter nucleoside pool and decrease ATP in mitochondria and lysosomes perturbing their homeostatic functions.[11] The reason for short stature and GH-IGF axis abnormalities, if any, in this syndrome are yet to be explored.

To date, we could find around 100 published cases of H syndrome, and around 80 of them had molecular confirmation. This should be considered as a remarkable number for a relatively novel autosomal-recessive disorder, which implies that the disorder is not as rare as it is thought to be.


Though it has been considered as a very rare disorder, this syndrome is probably undiagnosed, and hence unreported. The characteristic cutaneous manifestation along with genetic testing is the key to diagnosis. The hearing loss also varies in severity and can go unrecognized. Genetic testing is thus an essential tool to diagnose syndromic diabetes.


We acknowledge Prof. S. Ellard, Molecular Genetics Laboratory, Royal Devon and Exeter Hospital, Exeter, UK.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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