Case report of H-syndrome with a review from a rheumatological perspective
- Sandeep Yadav and
- Balakrishnan Canchi
- Rheumatology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India
- Correspondence to Dr Sandeep Yadav; sandy0751@gmail.com
Abstract
A woman in her 20s, symptomatic since the age of 4 with short stature, hearing loss, skin hyperpigmentation and induration over the medial aspect of the thigh, hypertrichosis, histiocytes on biopsy, lymphadenopathy, dilated scleral vessels, pancreatic exocrine deficiency, pericardial thickening, swelling of the eyelids and resistant retroperitoneal fibrosis. Whole-genome sequencing showed a mutation in SLC29A3, confirming ‘H’-syndrome. She is on steroids and methotrexate. This case highlights the rheumatological mimics of this rare disorder.
Background
H-syndrome is an autosomal recessive disorder of abnormal histiocyte proliferation caused by a mutation in SLC29A3. The first case was described in 2008,1 and since then, there have been 134 cases published in the literature.2 Its varied manifestations temporally evolve over time and may mimic many rheumatological manifestations, leading to diagnostic and therapeutic delays.3 We present one such case and highlight the rheumatological mimics of this novel disorder.
Case presentation
A woman in her 20s was symptomatic since the age of 4 when she began to have profound progressive sensorineural hearing loss. An MRI revealed bilateral cochlear calcification with no identifiable aetiology. She was treated with a cochlear implant. At the age of 16, she developed symmetrical hyper-pigmented induration of the skin along the medial aspects of both thighs. Skin biopsy revealed collagenous fibrosis in the dermis. She was treated as morphea with topical treatment without much response.
At the age of 20 years, she was diagnosed with short stature. Further testing revealed appropriate growth hormone levels, normal menarche and well-developed secondary sexual characteristics. She did not have diabetes. She did not receive any specific treatment. She developed occasional redness of the sclera from the age of 20–23 years, likely owing to scleral vein dilation.
At the age of 26 years, she weighed only 28 kg and was evaluated for intestinal malabsorption. She had a normal white cell count (WCC), with a haemoglobin of 83 g/L (mixed normocytic and microcytic), and iron studies were normal. There was low total protein, normal creatinine and spot urine protein creatinine ratio was 0.58. Erythrocyte Sedimentation rate (ESR) was 105 mm/hour, antinuclear antibody (ANA) by immunofluorescence was 1:80 positive (nucleolar pattern), and the ANA blot was negative. Duodenal biopsy was inconclusive. CT abdomen showed hyper-enhancing soft tissue in the region of the left renal pelvis extending along the course of the left ureter, compressing it, leading to hydronephrosis and also extending to bilateral (left >right) perinephric space (figure 1A). Scan also showed atrophy of the pancreas with fatty replacement, prominent retroperitoneal lymph nodes (8 mm) and pericardial thickening of 9.5 mm. Subsequent Ultrasonography (USG) guided biopsy of renal mass showed foamy histiocytes, epithelial aggregates with Touton cells, giant cells without any evidence of granulomas or malignancy. Immunostaining showed cells to be CD 68 positive, CD 1a negative, S 100 negative and IgG4 staining negative. Serum IgG4 level was normal. Based on the biopsy results, a diagnosis of idiopathic retroperitoneal fibrosis was made.
CT scan (A) sagittal section showing hyperintense mass involving the renal pelvis and perinephric space. (B) and (C) Transverse sections of abdomen taken 18 months apart showing an increase in the retroperitoneal mass even after treatment. (D) Tranverse section of chest showing pericardial thickening. (E) Transverse section of abdoment showing atrophy of pancreaswith fatty replacement. (F) Coronal section showing retroperitoneal mass compressing the pelvis and ureter.
In December 2019, methotrexate 15 mg per week and prednisolone 5 mg per day were started and continued for 18 months. Repeat scan done in July 2021 showed an increase in the size of the mass compared with the previous scans on the left side (cm): 8.5×7.5×5.6 (2019: 5.4×4.5×6.2) and right side(cm): 3.3×2.4×0.8 (from 2019: 2.6*2.1*5.1) (figure 1B,C). Since there was non-response to treatment, she was referred to the rheumatology department for further management of idiopathic retroperitoneal fibrosis.
On examination, she had short stature, sensorineural hearing loss, symmetrical induration and pigmentation of bilateral medial aspect of the thigh (figure 2A), hallux valgus (figure 2B) and periorbital swelling (lacrimal gland enlargement) (figure 2C).
Clinical images of the patient (A) pigmentation and induration over the medial aspect of the bilateral thigh (partial improved with treatment) (B) hallux valgus deformity of lower limb (C) enlargement of lacrimal gland.
Investigations
Investigatory reports were haemoglobin: 9.9 mg %, WCC: 7720/mm3, platelet: 3.47 lac/mm3, creatinine: 0.71 mg % and ESR: 55 mm at 1 hour. Based on these clinical and laboratory findings, we suspected the rare ‘H’-syndrome. Whole-genome sequencing was performed. It revealed a homozygous nonsense variant in SLC29A3 exon 6 (chr10: g.71362510G>T; depth: 122 ×) that results in a stop codon and premature truncation of the protein at codon 444 (p. Glu444Ter; ENST00000373189.6). Thus, H-syndrome was confirmed. The methotrexate dose was increased to 20 mg per week subcutaneous. She is planned for a repeat CT scan 6 months later to check for response
Discussion
H-syndrome is a rare autosomal recessive genodermatosis4 induced by an SLC29A3 gene mutation defined histologically by histiocyte prolifer
Flowchart showing the probable pathogenic mechanism in H-syndrome.
Histologically, H-syndrome is a type of histiocytosis . Histiocytosis5 are a group of disorders characterised by benign and malignant proliferation of monocytes, macrophages and dendritic cells in multiple tissues and organs, producing variable phenotype. The revised classification system6 includes five groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, (3) malignant histiocytosis, (4) Rosai-Dorfman disease and (5) haemophagocytic lympho-histiocytosis (HLH) and macrophage activation syndrome. It also includes certain inherited conditions like inherited Rosai Dorfman disease and HLH syndrome, caused by specific germline mutations and other rare familial histiocytosis.
Clinically, skin involvement is quite prevalent in H-syndrome, with cutaneous hyperpigmentation, hypertrichosis and induration found in 68% of patients.7 Other severe problems include valgus/flexion contracture (56%) and hearing loss (53%), low stature (short stature—49%), hepatosplenomegaly (43%), lymphadenopathy (23%), hyperglycaemia (23%, insulin-dependent diabetes mellitus) and hypogonadism (16%). Pericardial anomalies, pancreatic failure, eyelid oedema, varicose veins and facial telangiectasia have also been reported.
During the initial evaluation, the clinical picture of retroperitoneal and pericardial fibrosis, as well as foamy histiocytes on biopsy, indicated towards other histiocytic disorders of Erdheim Chester and Rosai Dorfman disease, which are caused by mutation in protooncogene B-raf serine/threonine kinases BRAF(V600E). However, in light of the other clinical finding and juvenile-onset symptoms, other inherited histiocytic illnesses were also considered, and genetic studies were later performed to indicate a characteristic SLCA29A3 mutation suggestive of H syndrome.
Similar to what Enver Simsek8 found in three Turkish siblings with H-syndrome, our patient had early-onset sensorineural hearing loss, hallux valgus (figure 2B), bilateral medial thigh hyperpigmentation/induration, hypertrichosis, dilated scleral vessels, short stature, microcytic hypochromic anaemia, raised inflammatory markers and SLC29A3 mutation. Our patient exhibited pericardial thickness instead of mitral valve/ Atrial Septal defect cardiac problems, did not have type I diabetes but did have a pancreatic exocrine deficiency and had normal secondary sexual characteristics, in contrast to theirs. These disparities underscore the disorder’s diverse phenotypic characteristics, despite shared genetic mutations.
Furthermore, it is important to highlight the fact that many features of ‘H’-syndrome may mimic inflammatory rheumatic disorders (see table 1).
Clinical characteristics and rheumatic mimics of our patient
| Characteristics of H-syndrome in our patients | Clinical feature that can be misdiagnosed as a rheumatological disorder |
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Skin pigmentation and induration in the skin can be treated like morphoea. Even the biopsy from skin lesions may show deposition of fibrous collagenous bundle making histopathological differentiation difficult without the clinical context, as seen in our case. Skin lesion being treated as morphoea has been reported by other authors.3 9 The clue to the diagnosis is skin pigmentation, and induration most commonly involves the medial aspect of the thighs7 symmetrically as classically seen in our case.
Hallux valgus and fixed flexion contractures of the toe and finger joints not seen in our patient can be wrongly treated as inflammatory arthritis, as reported by some authors.10 One author even reported the occurrence of bilateral sacroiliitis.11
In our case, patient came for a rheumatology opinion for resistant idiopathic retroperitoneal fibrosis treated as a probable IGG4-related disease. This is rare but has been reported.12 Similar histiocytic proliferation disorders like Erdheim Chester disease and Rosai Dorfman disease are known to cause retroperitoneal fibrosis and lymphadenopathy. H-syndrome is histologically similar to Rosai-Dorfman disease, with CD68 +S100+CD1 a—histiocytes and emperipolesis.13–15 Similarly, dilated scleral veins may be diagnosed as scleritis and swelling around the eyelid that may need workup to rule out IgG4-related disease, sarcoidosis and Sjogren’s syndrome.
Case reports of H-syndrome even mention the occurrence of Raynaud’s phenomena12 and digital ischaemia16 that may mimic vasculopathic inflammatory disorders. Other overlapping laboratory abnormalities that have been reported are haemolytic anaemia and pancytopenia.17 18 One author even reports telangiectasia, cytopenia and skin lesions treated as systemic lupus erythematosus.18
Thus, H-syndrome may be considered as monogenic autoinflammatory19 20 syndrome with fibrosing pathology,21 which may require immunosuppressive treatment. Literature regarding the treatment of H-syndrome is scarce, with most authors reporting inconsistent and overall poor or partial response to multiple immunosuppressants.18 Immunosuppressants that have been tried in treatment are systemic corticosteroids,22 methotrexate,23 Tumour necrosis factor (TNF) inhibitors,22 mycophenolate,24 thalidomide,18 interferon‐alpha, anakinra and tocilizumab.25 Despite this, the therapy regimens were ineffective or yielded partial results.2 Recent reports of promising responses to tocilizumab have been reported.25 With shared immunophenotypic features between H-syndrome and Rosai Dorfman disease/ECD,26 treatment options with other chemotherapeutic agents like cladribine, targeted therapy with BRAF and Mitogen-activated protein kinases MEK (Mitogen -activated protein kinases) inhibitors can be considered in resistant cases.27 28
Based on the current evidence, the most appropriate therapeutic approach will be to start with a steroid plus one of the other immunosuppressants, such as methotrexate or mycophenolate, and then switch on to tocilizumab or other targeted therapy agents if the response is poor.
Conclusion
H-syndrome is an autoinflammatory fibrosing inflammatory disorder associated with abnormal proliferation and defective reparative process in histocytes due to mutation in the SLC29A3 gene, leading to multiple clinical features evolving temporally over time and may mimic various inflammatory rheumatological disorders. To avoid diagnostic and treatment delays, rheumatologists and dermatologists should be aware of this disease and its various manifestations. Though the overall response is poor, newer therapy options such as IL-6 inhibitors show promise.
Learning points
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H-syndrome is a rare autosomal recessive inflammatory disorder characterised by abnormal proliferation of histiocytes.
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Its multiple clinical features like skin induration, joint arthropathy, retroperitoneal fibrosis, scleral vein dilatation, skin telangiectasias, and lacrimal gland enlargement may evolve temporally over time and may mimic various inflammatory rheumatological disorders.
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To avoid diagnostic and treatment delays, rheumatologists and dermatologists should be aware of this disease and its various manifestations.
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Though the overall response is poor, newer therapy options such as IL-6 inhibitors show promise.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @sandeepyadavsk
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Contributors SY and BC, both authors have contributed equally in conception, designing, defining the intellectual content, acquisition of data analysis and its interpretation. SY have done the literature review. SY and BC, both authors have contributed equally in drafting the manuscript, editing and reviewing it. SY and BC, both have approved the final version of the manuscript to be published and are in agreement to be accountable for the article and ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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