‘H-syndrome’: a multisystem genetic disorder with cutaneous clues

Abstract

We present a case of a 25-year-old man who came to our Endocrine Clinic for evaluation of short stature. He had a history of sensorineural hearing loss, hypertrichosis and hyperpigmentation with the thickening of the skin below the hip, gynecomastia and autoimmune haemolytic anaemia. Investigations showed that he had hypergonadotropic hypogonadism. His phenotype was consistent with that of a rare autosomal recessive genodermatosis of ‘H-syndrome’. The diagnosis was confirmed by genetic analysis using next-generation sequencing which showed a homozygous mutation in the SLC29A3 gene (variant: c.1330G>T (p.Glu444Ter)) which was confirmed by Sanger sequencing. This is a rare syndrome with around 100 cases reported in world literature. Though the skin manifestations are pathognomonic of the H-syndrome, it has myriad presentations like short stature, insulin-dependent diabetes mellitus, hypogonadism, hypothyroidism, dyslipidaemia, cardiac anomalies and sensorineural hearing loss. We report this case to highlight the constellation of features of this rare syndrome and bring awareness among the physicians to be vigilant about this syndrome.

Background

H-syndrome is a rare autoinflammatory genodermatosis with clinical manifestations involving multiple organ systems. The common clinical manifestations include hyperpigmentation, hypertrichosis, hallux valgus/flexion contractures, hearing loss, heart anomalies, hyperglycaemic/diabetes mellitus, low height (short stature), hepatosplenomegaly and hypogonadism. The distinctive feature of the disorder is cutaneous hyperpigmentation, hypertrichosis and induration commonly involving the inner thighs and shins with conspicuous sparing of the skin over the knee joint.^1–4

The syndrome is classified as OMIM #602782 under the broad spectrum of histiocytosis-lymphadenopathy plus syndrome. Histiocytosis-lymphadenopathy plus syndrome comprises of histiocytic disorders which were previously considered independent disorders—H-syndrome, Faisalabad histiocytosis, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome, sinus histiocytosis with massive lymphadenopathy and a mild and subtle variant of SLC29A3 disorder.^5–8 However, many patients with these disorders have overlapping manifestations, leading to the suggestion that they may be grouped under a broad syndrome of histiocytosis-lymphadenopathy plus syndrome (table 1).

Table 1.

Clinical manifestations of the related phenotypes

Clinical manifestations	PHID	SHML	FHC	H-syndrome	Mild SLC29A3 disorder	Manifestations in the index case
Cutaneous hyperpigmentation and hypertrichosis	+	−	−	+	−	+
Flexion contracture of fingers and toes	−	−	+	+	−	−
Hearing loss	−	+	+	+	+	+
Short stature	+	+	+	+	−	+
Hepatosplenomegaly	+	+	−	+	−	+
Cardiac anomalies	−	−	−	+	−	−
Genital masses/swelling with micropenis	−	−	+	+	−	+
Gynecomastia	−	−	−	+	−	+
Lymphadenopathy	+	+	+	−	+	−
Insulin-dependent diabetes mellitus	+	−	−	−	−	−
Hypogonadism (hypergonadotropic > hypogonadotropic)	−	−	+	+	−	+
Nasal infiltrates	−	+	+	−	−	−
SLC29A3 mutations	c.347T>G (p.Met116Arg), c.1330G>T (p.Glu444Ter), c.1309G>A (p.Gly437Arg), c.1346C>G (p.Thr449Arg)	c.1309G>A (p.Gly437Arg), c.300+1G>A	c.300+1G>A, c.1309G>A (p.Gly437Arg)	c.1279G>A (p.Gly427Ser), c.1309G>A (p.Gly437Arg), c.1088G>A (p.Arg363Gln), c.1087C>T (p.Arg363Trp), c.1157G>A (p.Arg386Gln)	c.243delA (p.Lys81Asnfs)	c.1330G>T (p.Glu444Ter)
References	Cliffe et al 10	Morgan et al 11	Morgan et al 11	Molho-Pessach et al 2	Bolze et al 12

A ‘+’ sign represents feature present.

A ‘−’ sign represents feature absent.

FHC, Faisalabad histiocytosis; PHID, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome; SHML, sinus histiocytosis with massive lymphadenopathy.

It is inherited as a homozygous or a compound heterozygous mutation of the SLC29A3 gene—solute carrier family 29 (nucleoside transporters) member 3 gene.² Histologically, skin lesions are characterised by dense cutaneous and subcutaneous infiltration of CD68+ histiocytes which are later replaced by fibrosis. There are around 100 cases of H-syndrome described in the literature, out of which only 10 have been reported from India.⁶ We intend to highlight the various clinical manifestations of this syndrome to the physicians to increase awareness about the same among the fraternity.

Case presentation

A 25-year-old man, of Asian Indian origin, attended the Endocrine Clinic for evaluation of short stature. He was born to non-consanguineous parents, with an uneventful perinatal period. His milestones were normal and he is a science graduate. At 5 years of age, the patient was diagnosed to have sensorineural hearing loss for which he was prescribed hearing aids. At 7 years of age, he was noticed to have hyperpigmentation and hypertrichosis with thickening of the skin below the hip (sparing the knee area). He developed gynecomastia at the age of 12 years and was also later diagnosed to have autoimmune haemolytic anaemia for which he was treated with steroids for 3 years which were gradually tapered and stopped.

On examination, he had short stature with a height of 135 cm (midparental height: 165 cm) and a weight of 40 kg (body mass index 21.95 kg/m²). General examination showed severely thick, oedematous (non-pitting) and hairy (hypertrichosis) lower limbs with conspicuous sparing around the knees. His sexual maturity rating was axillary hair (Tanner 3), pubic hair (Tanner 5) and bilateral firm testes of 2 mL volume (the thickening of the scrotal skin is seen as fullness in the picture) with a buried phallus. Gynecomastia (Tanner 3) was present bilaterally (figure 1).

Figure 1.

Figure showing hypertrichosis, hyperpigmentation and edematous skin of the medial thigh and genital region with gynecomastia.

Investigations

Important blood investigations showed normal haemogram, liver function tests and renal function tests. The patient’s hormonal profile was suggestive of hypergonadotropic hypogonadism (table 2).

Table 2.

Hormonal investigations of the patient

Laboratory parameter	Patient value	Normal range
Fasting blood sugar	89 mg/dL	74–99 mg/dL
HbA1C	4.5%	<5.7%
Luteinising hormone	32.10 mIU/mL	1.7–8.6 mIU/mL
Follicular-stimulating hormone	31.20 mIU/mL	1.5–12.4 mIU/mL
Testosterone	2.35 ng/mL	2.49–8.36 ng/mL
Prolactin	14.9 ng/mL	4.04–15.2 ng/mL
Thyroid-stimulating hormone	4.010 μIU/mL	0.35–5.50 μIU/mL
Free thyroxine	1.23 ng/dL	0.93–1.7 ng/dL

The patient’s chest radiograph was unremarkable and he had a normal 2D echocardiogram study. Ultrasound examination of the abdomen showed hepatosplenomegaly. Ultrasound and Doppler study of scrotum and perineum showed bilateral small testes (2 mL), subcutaneous oedema and thickening with coarse echogenicity. An audiogram confirmed moderate bilateral sensorineural hearing loss.

A skin biopsy performed from the medial aspect of the thigh showed diffuse, thickened collagen bundles in the dermis extending up to the subcutaneous region with histiocytic and lymphocytic infiltration. CD68 positivity was observed with immunohistochemical staining.

With the clinical features and laboratory parameters like hypertrichosis with hyperpigmentation, short stature, sensorineural hearing loss and hypergonadotropic hypogonadism, we considered the diagnosis of a rare genodermatosis of ‘H-syndrome’. The patient’s genetic analysis was performed using next-generation gene sequencing which showed a homozygous nonsense variation in exon 6 of the SLC29A3 gene (chr10:g.73122267G>T; Depth: 812x) that results in a stop codon and premature truncation of the protein at codon 444 (p.Glu444Ter; ENST00000373189.5). The observed variation lies in the nucleoside transporter domain of the SLC29A3 protein. Furthermore, Sanger sequencing was done to confirm the variant (figure 2). We wish to submit that although this variant is previously reported to be associated with the syndrome, the functional validation is yet to be documented. The latter carries significance as the mutation is in the last exon and there is a homozygous present in gnomAD.⁹ We concur that we were not able to do the functional studies due to the resource constraints at our end.

Figure 2.

Sanger sequencing report—sequence chromatogram and alignment to the reference sequence showing the variation in exon 6 of the SLC29A3 gene (chr10:g.73122267G>T; c.1330G>T; p.Glu444Ter) detected in the homozygous condition in the patient.

Treatment

Our patient was advised depot preparation of testosterone enanthate intramuscularly. He was prescribed hearing aids for sensorineural hearing loss.

Outcome and follow-up

He is currently being followed up and screened every 6 monthly for other manifestations of the H- syndrome like diabetes mellitus, cardiac anomalies and lower limb venous insufficiency.

Discussion

H-syndrome was first described by Molho-Pessach et al in 2008 in a group of Arab families.¹ The important manifestations include hypertrichosis and hyperpigmentation of the lower extremity, flexion contractures of fingers/camptodactyly, sensorineural hearing loss and short stature. Other manifestations are listed in table 1. Our patient had autoimmune haemolytic anaemia which has been reported only once in the literature.^1–4

H-syndrome is a monogenic, autosomal recessive genodermatosis. It is caused by a mutation in the solute carrier family 29 (nucleoside transporters) member 3 (SLC29A3) gene, which encodes the human equilibrative nucleoside transporter 3—which is present in the lysosomal and mitochondrial membranes and has a role in nucleoside transport across the membranes. It has been hypothesised that the ubiquitous presence of lysosomes and mitochondria throughout the body explains a wide range of presentation of the H-syndrome. However, the severity of the syndrome varies from mild skin manifestations to life-threatening complications even for similar mutation and hence there is a want of genotype–phenotype correlation of the disease.²

The management of H-syndrome involves treatment of individual manifestations like growth hormone therapy in childhood, testosterone replacement and artificial hearing aids. Though there is evidence of underlying inflammatory pathogenesis of the disease, there is a lack of consensus on the treatment of the primary pathology of the disease. Various agents like prednisolone, non-steroidal anti-inflammatory drugs, colchicine, cyclophosphamide and interleukin-1 inhibitors and tumour necrosis factor-α inhibitors have been tried with varying effect; however, the definitive treatment for the syndrome is still elusive.⁸

The phenotypic variability, rarity and relatively recent identification and characterisation of the disease may lead to non-diagnosis or misdiagnosis of this disorder. Though the pathognomonic features of H-syndrome are the skin manifestations, it may also manifest a constellation of other abnormalities like insulin-dependent diabetes mellitus, short stature, hypogonadism, camptodactyly, hearing loss, hypothyroidism, hypertriglyceridaemia and even very subtle manifestations. Hence, we report this case to highlight the multiple manifestations of this syndrome and bring awareness about the same in clinicians.

Patient’s perspective.

It took around 20 years from the onset of my first symptom to the actual diagnosis of H-syndrome. Though I understand and accept that there is currently no definitive cure for this syndrome, I am happy that I have been correctly diagnosed and have been started on testosterone therapy and hearing aids. I also understand that my case may be a tool to bring awareness amongst the physicians so that more and more of such cases are picked up and correctly treated for its various manifestations.

Learning points.

• H-syndrome is a rare genodermatosis with clinical manifestations involving multiple organs and organ systems. Hyperpigmentation, hypertrichosis, hallux valgus/flexion contractures, hearing loss, heart anomalies and hepatosplenomegaly being the common ones among its many presentations. Insulin-dependent diabetes mellitus, short stature, hypogonadism, amenorrhoea, microphallus, infertility, hypothyroidism and hypertriglyceridaemia are a few of the endocrine manifestations of H-syndrome.

• The recent identification and characterisation of the syndrome, the phenotypic variability and rarity of the condition may lead to non-diagnosis or misdiagnosis of the condition.

• There is a need for heightened awareness among clinicians for early recognition of this syndrome.