Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome
-
Senthil Senniappan
Abstract
Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-α was ineffective.
References
1. Hussain K, Padidela R, Kapoor RR, James C, Banerjee K, et al. Diabetes mellitus, exocrine pancreatic deficiency, hypertrichosis, hyperpigmentation, and chronic inflammation: confirmation of a syndrome. Pediatr Diabetes 2009;10:193–7.10.1111/j.1399-5448.2008.00470.xSearch in Google Scholar PubMed
2. Prendiville J, Rogers M, Kan A, de Castro F, Wong M, et al. Pigmented hypertrichotic dermatosis and insulin dependent diabetes: manifestations of a unique genetic disorder? Pediatr Dermatol 2007;24:101–7.10.1111/j.1525-1470.2007.00352.xSearch in Google Scholar PubMed
3. Cliffe ST, Kramer JM, Hussain K, Robben JH, de Jong EK, et al. SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway. Hum Mol Genet 2009;18: 2257–65.10.1093/hmg/ddp161Search in Google Scholar PubMed
4. Molho-Pessach V, Agha Z, Aamar S, Glaser B, Doviner V, et al. The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. J Am Acad Dermatol 2008;59:79–85.10.1016/j.jaad.2008.03.021Search in Google Scholar PubMed
5. Morgan NV, Morris MR, Cangul H, Gleeson D, Straatman-Iwanowska A, et al. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS Genet 2010;6: e1000833.10.1371/journal.pgen.1000833Search in Google Scholar PubMed PubMed Central
6. Spiegel R, Cliffe ST, Buckley MF, Crow YJ, Urquhart J, et al. Expanding the clinical spectrum of SLC29A3 gene defects. Eur J Med Genet 2010;53:309–13.10.1016/j.ejmg.2010.06.012Search in Google Scholar PubMed
7. Molho-Pessach V, Lerer I, Abeliovich D, Agha Z, Abu Libdeh A, et al. The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am J Hum Genet 2008;83:529–34.10.1016/j.ajhg.2008.09.013Search in Google Scholar PubMed PubMed Central
8. Molho-Pessach V, Suarez J, Perrin C, Chiaverini C, Doviner V, et al. The H syndrome: two novel mutations affecting the same amino acid residue of hENT3. J Dermatol Sci 2010;57:59–61.10.1016/j.jdermsci.2009.09.011Search in Google Scholar PubMed
9. Elbarbary NS, Tjora E, Molnes J, Lie BA, Habib MA, et al. An Egyptian family with H syndrome due to a novel mutation in SLC29A3 illustrating overlapping features with pigmented hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad histiocytosis. Pediatr Diabetes 2012. doi: 10.1111/j.1399-5448.2012.00925.x [Epub ahead of print].10.1111/j.1399-5448.2012.00925.xSearch in Google Scholar PubMed
10. Marcu CB, Niessen HW, Beek AM, Brouwer WP, Robbers LF, et al. Cardiac involvement with amyloidosis: mechanisms of disease, diagnosis and management. Conn Med 2011;75:581–90.Search in Google Scholar
11. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore) 2003;82:129–46.10.1097/00005792-200303000-00007Search in Google Scholar PubMed
12. Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendínez F, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 2010;62:489–95.10.1016/j.jaad.2009.04.046Search in Google Scholar PubMed
13. Torrelo A, España A, Boixeda P, Ledo A. Partial lipodystrophy and dermatomyositis. Arch Dermatol 1991;127:1846–7.10.1001/archderm.1991.04520010088019Search in Google Scholar
14. Mallewa JE, Wilkins E, Vilar J, Mallewa M, Doran D, et al. HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 2008;62:648–60.10.1093/jac/dkn251Search in Google Scholar PubMed
15. Brown TT. Approach to the human immunodeficiency virus-infected patient with lipodystrophy. J Clin Endocrinol Metab 2008;93:2937–45.10.1210/jc.2008-1019Search in Google Scholar PubMed PubMed Central
16. Kang N, Jun AH, Bhutia YD, Kannan N, Unadkat JD, et al. Human equilibrative nucleoside transporter-3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization, and stability. J Biol Chem 2010;285:28343–52.10.1074/jbc.M110.109199Search in Google Scholar PubMed PubMed Central
17. Doviner V, Maly A, Ne’eman Z, Qawasmi R, Aamar S, et al. H syndrome: recently defined genodermatosis with distinct histologic features: a morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases. Am J Dermatopathol 2010;32:118–28.10.1097/DAD.0b013e3181b28572Search in Google Scholar PubMed
18. Hsu CL, Lin W, Seshasayee D, Chen YH, Ding X, et al. Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis. Science 2012;335:89–92.10.1126/science.1213682Search in Google Scholar PubMed
19. Melki I, Lambot K, Jonard L, Couloigner V, Quartier P, et al. Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition. Pediatrics 2013;131:e1308–13.10.1542/peds.2012-2255Search in Google Scholar PubMed
20. Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell 2010;140:784–90.10.1016/j.cell.2010.03.002Search in Google Scholar PubMed PubMed Central
©2013 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- Masthead
- Masthead
- Review article
- Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review
- Images in pediatric endocrinology
- Solitary median maxillary central incisor, a clinical predictor of hypoplastic anterior pituitary, ectopic neurohypophysis and growth hormone deficiency
- A rare case of granuloma annulare in a 6-year-old child with type 1 diabetes
- Original articles
- The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency
- The relationship between adiposity and stature in prepubertal children with celiac disease
- Influence of micronutrient status and socioeconomic gradient on growth indices of 2–18-year-old Indian girls
- Phosphotyrosine phosphatases in GH-stimulated skin fibroblasts from children with idiopathic short stature
- The relation between salivary cortisol and the metabolic syndrome score in girls
- Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea
- Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children
- Characteristics of infants at risk of hypoglycaemia secondary to being ‘infant of a diabetic mother’
- Parental dyadic coping in families of children and adolescents with type 1 diabetes
- Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome
- Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA
- Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias
- Sexual development in prepubertal obese boys: a 4-year longitudinal study
- Genetic diagnosis of one family with incomplete clinical data
- Patient reports
- Complete androgen insensitivity syndrome and discordant Müllerian remnants: two cases with novel mutation in the androgen receptor
- Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture
- Ambiguous genitalia in a 48, XXYY newborn: a casual relationship or a coincidence?
- Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens
- Significant testicular enlargement in a 6.5-year-old boy with monorchism and testicular microlithiasis
- Report of the first case of precocious puberty in Rett syndrome
- Type II vitamin D-dependent rickets with diabetic ketoacidosis
- Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent
- A rare association between Rathke’s cyst and hypophysitis in a patient with delayed sex development and growth failure
- Diabetes mellitus with Laron syndrome: case report
- Wegener granulomatosis as an uncommon cause of panhypopituitarism in childhood
- Rare cases of autoimmune hypothyroidism in young children
- Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF
- Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy
- Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease
- Virilization in two pre-pubertal children exposed to topical androgen
- A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands
- Short communications
- Plasma ceramides are elevated in female children and adolescents with type 2 diabetes
- Assessment of contractility and myocardial function in small and appropriate for gestational age premature neonates using the stress-velocity relationship and tissue Doppler imaging immediately after birth
- Letter to the Editors
- Homeostasis model assessment of insulin resistance may not be reliable to evaluate insulin sensitivity in young obese children
- Type 1 diabetes in women with endometriosis: what is the risk of occurrence?
- How should we manage vitamin D-deficient adolescents?
- Should neonatal hyperparathyroidism associated with mucolipidosis II/III be treated pharmacologically?a
Articles in the same Issue
- Masthead
- Masthead
- Review article
- Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review
- Images in pediatric endocrinology
- Solitary median maxillary central incisor, a clinical predictor of hypoplastic anterior pituitary, ectopic neurohypophysis and growth hormone deficiency
- A rare case of granuloma annulare in a 6-year-old child with type 1 diabetes
- Original articles
- The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency
- The relationship between adiposity and stature in prepubertal children with celiac disease
- Influence of micronutrient status and socioeconomic gradient on growth indices of 2–18-year-old Indian girls
- Phosphotyrosine phosphatases in GH-stimulated skin fibroblasts from children with idiopathic short stature
- The relation between salivary cortisol and the metabolic syndrome score in girls
- Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea
- Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children
- Characteristics of infants at risk of hypoglycaemia secondary to being ‘infant of a diabetic mother’
- Parental dyadic coping in families of children and adolescents with type 1 diabetes
- Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome
- Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA
- Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias
- Sexual development in prepubertal obese boys: a 4-year longitudinal study
- Genetic diagnosis of one family with incomplete clinical data
- Patient reports
- Complete androgen insensitivity syndrome and discordant Müllerian remnants: two cases with novel mutation in the androgen receptor
- Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture
- Ambiguous genitalia in a 48, XXYY newborn: a casual relationship or a coincidence?
- Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens
- Significant testicular enlargement in a 6.5-year-old boy with monorchism and testicular microlithiasis
- Report of the first case of precocious puberty in Rett syndrome
- Type II vitamin D-dependent rickets with diabetic ketoacidosis
- Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent
- A rare association between Rathke’s cyst and hypophysitis in a patient with delayed sex development and growth failure
- Diabetes mellitus with Laron syndrome: case report
- Wegener granulomatosis as an uncommon cause of panhypopituitarism in childhood
- Rare cases of autoimmune hypothyroidism in young children
- Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF
- Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy
- Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease
- Virilization in two pre-pubertal children exposed to topical androgen
- A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands
- Short communications
- Plasma ceramides are elevated in female children and adolescents with type 2 diabetes
- Assessment of contractility and myocardial function in small and appropriate for gestational age premature neonates using the stress-velocity relationship and tissue Doppler imaging immediately after birth
- Letter to the Editors
- Homeostasis model assessment of insulin resistance may not be reliable to evaluate insulin sensitivity in young obese children
- Type 1 diabetes in women with endometriosis: what is the risk of occurrence?
- How should we manage vitamin D-deficient adolescents?
- Should neonatal hyperparathyroidism associated with mucolipidosis II/III be treated pharmacologically?a
