Rare Types of Diabetes

Clustering of diabetes and additional autoimmune disease may be caused by a mutation within a single gene. These monogenic autoimmune syndromes show highly variable phenotypes, but generally have an earlier onset and more severe phenotype than common polygenic autoimmunity. A genetic diagnosis may inform medical management, give insight into prognosis and inform families of recurrence risk.

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We offer testing free of charge¹ on a research basis for 15 known monogenic autoimmune genes (AIRE, CD55, CTLA4, DOCK8, FOXP3, IL2RA, ITCH, JAK1, LRBA, NFKB1, SIRT1, SLC29A3, STAT1, STAT3, STAT5B and TNFAIP3) via targeted next generation sequencing. We welcome samples from any patient diagnosed with diabetes and at least one additional autoimmune disorder before the age of five years, no matter what their age is now. In patients without a mutation, gene discovery studies by whole genome sequencing may be employed in order to find the aetiological cause of their disease.

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Please fill in the multiple autoimmunity request form (link below) and send with samples. Details of sample requirements and the postal address can be found on the request form. We would strongly recommend sending blood or DNA from both parents as well as the child, as this will allow us to establish rapidly that a genetic mutation is likely to be the cause of the diabetes and autoimmune disease if it has arisen de novo and not present in either unaffected parent.

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Genetic Test Referral Forms

 ¹ Possible through funding from the Wellcome Trust in the form of a Senior Investigator Award to Professors Hattersley and Ellard.

 

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome – FOXP3

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is an X-linked disorder affecting only males. It is the cause of neonatal diabetes in 3.5% of boys diagnosed with diabetes before the age of 6 months and tested in Exeter.

Disease phenotype

The most common feature of IPEX syndrome is enteropathy which presents as severe protein losing diarrhoea and can be life threatening. Diabetes usually follows and is often diagnosed in the first six months of life, and severe skin rashes are common. The majority of individuals present extremely early with aggressive autoimmunity however a less severe phenotype has been reported in some families where early-onset diabetes may be the only feature. Recent studies suggest that the disease manifestations of IPEX syndrome are broad and variable and it is therefore likely to be underdiagnosed. Individuals with IPEX syndrome usually have raised serum IgE, and testing should be considered for males presenting with early-onset autoimmunity (diagnosed <5 years) and raised IgE.

Genetics 

Recessively acting loss-of-function mutations in FOXP3 cause IPEX syndrome.  As FOXP3 is located on the X chromosome a single copy of a mutation (hemizygosity) is sufficient to cause disease in males. There is often no family history of IPEX syndrome as the patient will have inherited their X chromosome, and hence FOXP3 mutation, from their unaffected mother who has both a normal and mutated copy of the gene.

Medical management 

Haematopoietic stem cell transplant (HSCT) can be curative for IPEX syndrome. In order to prevent non-reversible damage to the endocrine system, particularly the beta cells, early pre-emptive HSCT may be necessary. Diabetes can be difficult to manage in patients with IPEX syndrome due to the co-existence of severe enteropathy. Whilst parenteral nutrition may combat the effects of severe protein-losing diarrhoea it generally has limited success. Immunosuppressive therapy is often required to manage the enteropathy, with Sirolimus offering a targeted approach.  Dermatological manifestations are managed by topical treatment with steroids and pain management. 

References

Rubio-Cabezas O, Minton JA, Caswell R, Shield JP, Deiss D, Sumnik Z, et al. Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. Diabetes Care. 2009 Jan;32(1):111-6.

McMurchy AN, Gillies J, Allan SE, Passerini L, Gambineri E, Roncarolo MG, et al. Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked have diverse abilities to reprogram T cells into regulatory T cells. J Allergy Clin Immunol. 2010 Dec;126(6):1242-51.

Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002 Aug;39(8):537-45.

Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severity. Journal of Allergy and Clinical Immunology. 2008 12//;122(6):1105-12.e1.

Xavier-da-Silva MM, Moreira-Filho CA, Suzuki E, Patricio F, Coutinho A, Carneiro-Sampaio M. Fetal-onset IPEX: report of two families and review of literature. Clin Immunol. 2015 Feb;156(2):131-40.

Powell BR, Buist NRM, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. The Journal of Pediatrics. 1982;100(5):731-7.

Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome. The Journal of Clinical Investigation. 2000;106(12):R75-R81.

Common Variable Immunodeficiency-8 with Autoimmunity (CVID-8) – LRBA

CVID-8 is caused by recessively inherited mutations in the LRBA gene, and mostly affects consanguineous families (patients who have parents that are related), although this is not always the case.

Disease Phenotype

Around a third of patients with LRBA mutations develop early-onset diabetes which can present in the neonatal period. Common features of CVID-8 are autoimmune haematological diseases (including thrombocytopenia, autoimmune haemolytic anaemia and lymphoproliferative syndromes), iInflammatory bowel disease and thyroid autoimmunity individuals. Immunodeficiency is also a common feature of this disorder with frequent and recurrent infections resulting from hypogammaglobulinaemia. Clinically, CVID-8 is a heterogeneous disease with the phenotype ranging from severe multiple early-onset autoimmunity through to isolated irritable bowel disease.

Medical management

Personalised medicine is available for these individuals in the form of Abatacept™, a CTLA4-immunoglobulin fusion drug. Patients with LRBA mutations have been effectively treated with Abatacept™, which resultsin a dramatic improvement in inflammatory and autoimmune symptoms with long term treatment (5-8 years duration)  Blood transfusions can treat prolonged cytopenic episodes with intravenous immunoglobulin therapy administered to reduce infections associated with hypogammaglobulinaemia. Several patients have been successfully treated with haematopoietic stem cell transplantation.

References

Johnson MB, De Franco E, Lango Allen H, Al Senani A, Elbarbary N, Siklar Z, Berberoglu M, Imane Z, Haghighi A, Razavi Z, Ullah I, Alyaarubi S, Gardner D, Ellard S, Hattersley AT, Flanagan SE. Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes. Diabetes. 2017 Aug;66(8):2316-2322

Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, Herholz P, Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012 Jun 8;90(6):986-1001.

Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012 Aug;130(2):481-8 e2.

Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol. 2012 Dec;130(6):1428-32.

Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clinical Immunology. 2015 7//;159(1):84-92.

Serwas NK, Kansu A, Santos-Valente E, Kuloglu Z, Demir A, Yaman A, et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflammatory bowel diseases. 2015 Jan;21(1):40-7.

Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015 Jan;135(1):217-27.

Infancy-Onset Multi-system Autoimmune Disease – STAT3

Disease Phenotype

Dominantly acting germline gain-of-function mutations in STAT3 cause Infantile-onset multisystem autoimmune disease. These individuals may present with neonatal diabetes (diagnosed in the first 6 months), which is seen in about 20% of reported individuals. Autoimmune lymphoproliferative disease and haematological disorders are commonly seen in these patients. Additional features include short stature (< 5th centile), enteropathy and recurring infections.

A family history of autoimmunity suggesting dominant inheritance may be present, although many individuals do not have a family history as the STAT3 mutation has arisen de novo (not present in the parents).

Screening of STAT3 should be considered in all patients with neonatal diabetes (diagnosed <6 months) and in individuals presenting with early-onset autoimmune lymphoproliferation and recurrent infections. In older children, short stature combined with autoimmunity may be considered. 

Medical management

Immune suppression may be useful to treat the severe autoimmune disease. Haematopoietic stem cell transplantation has been performed in some patients with gain of function STAT3 mutations and can be curative.  There has been some progress in the development of targeted therapies for these individuals; for one patient with severe polyarthritis and scleroderma, treatment with a monoclonal antibody that blocks IL-6 resulted in a marked improvement in acute arthritic and dermatological symptoms.

References

Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Lango Allen H, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014 Aug;46(8):812-4.

Haapaniemi EM, Kaustio M, Rajala HL, van Adrichem AJ, Kainulainen L, Glumoff V, et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood. 2015 Jan 22;125(4):639-48.

Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015 Jan 22;125(4):591-9

Wienke J, Janssen W, Scholman R, Spits H, van Gijn M, Boes M, et al. A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation. Oncotarget. 2015 Aug 21;6(24):20037-42.

Other forms of monogenic autoimmunity

Autoimmune Polyendocrinopathy Syndrome type 1 – AIRE

Autoimmune Polyendocrinopathy syndrome type 1 (APS1, also known as APECED – Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) is most commonly caused by recessively inherited loss-of-function mutations in the autoimmune regulator gene, AIRE. Increased rates of APS1 are observed in the Finnish (1:25,000) and Sardinian (1:14,000) populations as a result of founder mutations and also in the Jewish Iranians (1:9000) which is likely to reflect the high rate on consanguineous unions within this population. Dominant negative missense mutations have also been reported in some families with APS1. Patients with dominantly acting mutations often show a less severe phenotype compared to those with recessive mutations.

Disease Phenotype

APS1 presents early in childhood (median age: 3.3 years) and is characterised by three major components; chronic mucocutaneous candidiasis is usually the presenting feature which is followed by the development of hypoparathyroidism and later autoimmune adrenal insufficiency (see table 2). Type 1 diabetes which is present in 13% of individuals at 30 years, and autoimmune hepatitis affects 20% of individuals at 18 years. Gonadal insufficiency occurs in approximately 50% of individuals with APS1 and is usually primary. Alopecia is present in 39% of adults and ectodermal dystrophies are common with dental enamel hypoplasia identified in 77% of individuals in one large series. Rarer disease components may dominate the clinical picture.

Medical management

Treatment for APS1 focusses on the management of the individual components of the syndrome. The prognosis depends predominantly on the effective treatment of endocrine deficiencies, the management of which is particularly challenging in some individuals due to the co-existence of type 1 diabetes, adrenal insufficiency and/or autoimmune thyroid disease. Dietetic management to maintain electrolyte balance is often necessary and parenteral feeding may be required for patients with severe malabsorption due to enteropathy. Combined systemic and topical treatments are used to combat chronic mucocutaneous candidiasis. For some patients with severe enteropathy or autoimmune hepatitis immune suppressive therapy is required. Early detection of autoimmune disease can assist in treatment optimisation, therefore educating patients on the chronic features of APS-1 is important.

References

Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009 May;265(5):514-29.

Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006 Aug;91(8):2843-50.

Valenzise M, Fierabracci A, Cappa M, Porcelli P, Barcellona R, De Luca F, et al. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Report of Seven Additional Sicilian Patients and Overview of the Overall Series from Sicily. Hormone Research in Paediatrics. 2014;82(2):127-32

Immunodeficiency 41 with lymphoproliferation and autoimmunity – IL2RA

Disease Phenotype

Immunodeficiency 41 with lymphoproliferation and autoimmunity is caused by recessively inherited mutations in the IL2RA gene. It is characterised by extremely early presentation in the neonatal period with severe enteropathy leading to malabsorption and failure to thrive, and chronic and recurring cytomegalovirus (CMV) infection. Additional autoimmunity including type 1 diabetes, hypothyroid disease, dermatological manifestations and alopecia are common features typically presenting in infancy and early childhood.

Medical management

Haematopoietic stem cell transplantation has proved successful in one case with a complete remission of autoimmune symptoms achieved following treatment. Prophylactic treatment with a combination of antibiotics is prudent as these individuals have a reduced ability to fight infections and to mount an adaptive response to previously encountered pathogens. Immunosuppressive therapy is required to treat severe and chronic autoimmunity and may have some effect in improving symptoms particularly those resulting from enteropathy. Sirolimus is the immunosuppressive of choice as this drug preferentially targets effector T cells over regulatory T cells which have reduced suppressive function in these individuals.

References

Bezrodnik L, Caldirola MS, Seminario AG, Moreira I, Gaillard MI. Follicular bronchiolitis as phenotype associated with CD25 deficiency. Clin Exp Immunol. 2014 Feb;175(2):227-34.

Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013 Mar;146(3):248-61.

Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proceedings of the National Academy of Sciences. 1997 April 1, 1997;94(7):3168-71.

Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatric research. 2000 Jul;48(1):6-11.

Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007 Feb;119(2):482-7.

Genetic Testing

We offer testing free of charge1 on a research basis for 15 known monogenic autoimmune genes (AIRE, CD55, CTLA4, DOCK8, FOXP3, IL2RA, ITCH, JAK1, LRBA, NFKB1, SIRT1, SLC29A3, STAT1, STAT3, STAT5B and TNFAIP3) via targeted next generation sequencing. We welcome samples from any patient diagnosed with diabetes and at least one additional autoimmune disorder before the age of five years, no matter what their age is now. In patients without a mutation, gene discovery studies by whole genome sequencing may be employed in order to find the aetiological cause of their disease.

Please fill in the multiple autoimmunity request form (link below) and send with samples. Details of sample requirements and the postal address can be found on the request form. We would strongly recommend sending blood or DNA from both parents as well as the child, as this will allow us to establish rapidly that a genetic mutation is likely to be the cause of the diabetes and autoimmune disease if it has arisen de novo and not present in either unaffected parent.

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MDP syndrome (Mandibular hypoplasia, Deafness and Progeroid features), is an extremely rare metabolic disorder that prevents fatty tissue from being stored underneath the skin. It is only known to affect a very small number of people worldwide (less than 10 cases have been diagnosed to date). Recent research has shown it is caused by a change in the POLD1 gene on chromosome 19, which affects an enzyme crucial to DNA replication.

Summary of the features of MDP syndrome

• mandibular hypoplasia (a small lower jaw),
• deafness,
• tightening of the skin,
• lipodystrophy (a reduction in fat under the skin),
• low testosterone levels in males,
• contractures of the long tendons of the toes resulting in claw toes and joint stiffness.

Making a diagnosis

The diagnosis of MDP syndrome is suggested by the clinical features (Shastry 2010). It can be confirmed by finding a mutation in the POLD1 gene, a service offered by the Molecular Genetics team at the Royal Devon University Healthcare NHS Foundation Trust / Exeter University who originally discovered the genetic cause.

Genetics Initially all people we have identified with this syndrome have an identical genetic change, an inframe single codon deletion in POLD1 resulting in a loss of Serine at position 605 (Weedon 2013) The POLD1 gene is expressed in all cells and the particular change seen in most patients results in loss of DNA polymerase activity but only mildly impairs the proof reading exonuclease activity. Recently there has been a second genetic change reported in an Italian patient, a novel heterozygous mutation in exon 13 (R507C)(Pelosini 2014).

Most cases identified to date have been caused by a spontaneous genetic change (so the parents of the individual are unaffected).

Clinical features and their management

1. General appearance

Appearance at birth and during the early years is normal but features become more prominent during later childhood prior to puberty. The main issues appear to be lipodystrophy (see below) and slow growth of cartilage and ligaments. The slow growth of cartilage and ligamentsresults in a small nose, small mandible (jaw), small ears and tightening of ligaments in the limbs. A small larynx (due to

the reduced growth of cartilage) can mean the voice is likely to remain high pitched (even in boys after puberty).

2. Lipodystrophy

A major feature is lipodystrophy (a reduction in fat under the skin). The characteristic changes in facial appearance occur from the loss of fat from the cheeks, and around the eyes .Dry eyes and the failure to close eyes during sleep can be a feature due to the loss of fat around the eyes (rather than any excessive prominence of the eyeballs). Limbs appear very thin due to lack of fat storage and also reduced muscle mass. There is a large amount of fat within the abdominal cavity which, can be particularly marked in the liver (but not always) and surrounds the other organs. A major result of the lipodystrophy in some people is severe insulin resistance so insulin does not work very well leading to diabetes and high triglyceride levels in the blood. The effect of insulin resistance can be variable and may relate to progression of the lipodystrophy or may reflect variation between individuals.

The skin has a lack of lack of fat and fibrosis. These in turn result in the tight skin on the face and limbs. One direct feature of the lipodystrophy is that the skin is fragile and there is not the protection normally provided by fat under the skin.

Familial Partial Lipodystrophy (FPLD) is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently.

Cambridge SIR

2.1 Management of lipodystropy

As fat cannot be stored under the skin it is important to have a healthy diet without excess fat. Often due to failure to thrive or lack of subcutaneous fat there may have been encouragement to add supplements or fat to the diet however this will not result in any increase in fat under the skin and can easily result in it going into tissues such as the liver or kidney where it is not desired. In people with moderate / severe lipodystrophy we would recommend a low fat diet but in those where the lipodystrophy has not progressed (for example in younger children) a healthy relatively low fat diet may be sufficient. The fat and muscle reduction is not the result of dietary insufficiency and cannot be treated with dietary measures. Apart from diet the other thing that is important is exercise which should be encouraged and will make insulin work more effectively.

In those who have not developed diabetes we recommend fasting insulin, triglycerides, glucose and HbA1c should be measured annually to monitor insulin resistance and blood glucose.

In those with diabetes we would suggest using Metformin in doses of at least 2g/day as it decreases insulin resistance and improves insulin sensitivity.

The thin skin means if there is trauma there should be rapid attention to any wounds to avoid infection and help primary healing as there can be problems with skin ulcers.

3. Low Testosterone/Hypogonadism in males

Some males have had undescended testes but in all cases, whether or not this was corrected, they have hypogonadism (reduced function of the testes) and many may be infertile due to inadequate testicular development. In females normal periods have been observed.

Low testosterone will require testosterone replacement. In peri-pubertal males, adequate testosterone replacement is required for its anabolic affects such as growth and also the induction of

puberty with high doses. This needs to be coordinated with growth hormone replacement (if given) to avoid early closure of the epitheses (ends of the bones) which would reduce height.

4. Growth

Although in the original clinical description short stature was included in the characteristics of MDP syndrome, looking at the data closely it showed that many patients were well within the normal range. If growth is of concern growth hormone therapy could be considered and coordinated with testosterone replacement where appropriate.

5. Deafness

Deafness is a feature of MDP syndrome as a result of the nerves not working well and people often have difficulty getting hearing aids because of the small size of their ears. Digital hearing aids can be helpful and audiometry follow up will be needed.

6. Feet/contractures

There may be different problems associated with MDP syndrome in the feet. The lack of subcutaneous fat means that there is direct pressure on the skin resulting in callus (hard skin) on the heels and also the weight-bearing parts of the forefoot. This is best managed by trying to find insoles to support the foot but it’s difficult to avoid completely. There is no approach that will increase the subcutaneous fat. The second feature is clawed toes as a result of contraction of the long extender tendons. The contractured constrictions can get worse over time. It is worth considering a physiotherapy referral with an aim to establish exercises to try and keep the tendons stretched if possible.

7. Dental

The failure of growth of the mandible (lower jaw) can rapidly result in dental overcrowding. In this case it is best to remove teeth early rather than hoping that there will be mandibular (lower jaw) growth. Overcrowding can result in the teeth being severely displaced and again it is best to act early because later correction orthodontically can be extremely difficult.

8. Development

Many people with MDP syndrome are high achievers intellectually following careers in law, medicine and computing. A crucial point is that they do not have progeria and there is no evidence of accelerated intellectual decline with age in these patients. Equally life expectancy has not been shown to be reduced. Patients of 65 have been described in the literature and none of the patients are known to have malignancy. Therefore there are many crucial differences with progeria and the name of progerioid in the title is confusing as this really refers to the lack of fat in the face and taut skin and not any intellectual or other age associated features.

General

It is helpful to co-ordinate clinical care as much as possible, this may be managed best by a consultant endocrinologist as the most active management is going to relate to the management of

lipodystrophy, insulin resistance, diabetes and testosterone replacement therapy and growth hormone replacement if required. Other local specialists could provide care when this is needed.

If there are any questions relating to any aspects of care we would be happy to try and provide information from other patients with the same condition. Clearly this is a recently described syndrome and we are all learning from experiences with different patients. Please pass this information on to other people involved in your (or your patient’s) care. If you are a health care professional we would be very grateful if we could be copied in on clinic letters so we are kept up to date with progress.

If you would like further information please contact us here:

Contact us

References

Pelosini Caterina, Martinelli Silvia, Ceccarini Giovanni, Magno Silvia, Barone Ilaria, Basolo Alessio, Fierabracci Paola, Vitti Paolo, Maffei Margherita, Santini Ferruccio, Identification of a novel mutation in the Polymerase Delta 1 (POLD1) gene in a lipodystrophic patient affected by Mandibular Hypoplasia, Deafness, Progeroid Features (MDPL) syndrome, Metabolism (2014), doi: 10.1016/j.metabol.2014.07.010

Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, Novelli G, Kroiss M, Garg A. A Novel Syndrome of Mandibular Hypoplasia, Deafness, and Progeroid Features Associated with Lipodystrophy, Undescended Testes, and Male Hypogonadism. J Clin Endocrinol Metab. Oct 2010; 95(10): E192–E197.

Weedon MN1, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G, Turnpenny P, McCann E, Goh KJ, Wang Y, Fulford J, McCulloch LJ, Savage DB, O’Rahilly S, Kos K, Loeb LA, Semple RK, Hattersley AT. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.Nat Genet. 2013 Aug;45(8):947-50. doi: 10.1038/ng.2670. Epub 2013 Jun 16.

Type A Insulin Resistance

Donohue syndrome (leprechaunism)

A congenital syndrome characterised by growth retardation, dysmorphic facies, severe insulin resistance and lipoatrophy.

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Rabson-Mendenhall Syndrome

Less severe than Leprechaunism, with a longer life expectancy and less severe growth retardation. Clinical features include dystrophic nails and teeth and precocious puberty.

Scientific Information

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Partial Lipodystrophy

Genetic Testing in Wolfram Syndrome

Wolfram syndrome is an autosomal recessive condition that is typically associated with childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy. In addition, people with Wolfram syndrome may also develop diabetes insipidus, sensorineural hearing loss, bladder dysfunction and neurological, psychiatric and behavioural problems.  

The symptoms and rate of progression of Wolfram syndrome can be quite variable. Most of those affected by Wolfram syndrome develop insulin-dependent diabetes mellitus and optic atrophy before the age of 16 (>80%).

Wolfram syndrome is caused by biallelic mutations in the WFS1 (most common) or CISD2 genes.  Rare dominant acting mutations in WFS1 have been reported to cause a specific syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts (De Franco et al 2017 Diabetes 66: 2044-2053).

The clinical diagnosis of Wolfram syndrome is based on the presence of childhood onset diabetes mellitus and progressive optic atrophy, and confirmed by the finding of a biallelic mutation in the WFS1 or CISD2 gene.  Mutation analysis of the WFS1 and CISD2 genes is offered by the Exeter Genomics Laboratory as part of the targeted next generation sequencing service for monogenic diabetes.   Analysis of WFS1 is also offered by the West Midlands Regional Genetics Laboratory, and Dr Tim Barrett runs a multidisciplinary paediatric clinic at Waterfall House, Birmingham Children’s Hospital for patients with a suspected or confirmed diagnosis of Wolfram Syndrome (see https://bwc.nhs.uk/wolfram-syndrome for details).

For further clinical advice and support, please contact:

Dr Tim Barrett
Children Nationwide Senior Lecturer Paediatrics
Diabetes Unit
Birmingham Children’s Hospital
Steelhouse Lane
Birmingham
B4 6NH

Email: t.g.barrett@bham.ac.uk

Wolfram Syndrome website

Hardy H, Khanim F, Torres R, Scott-Brown M, Sellar A, Poulton J, Collier D, Kirk J, Polymeropoulos M, Latif F, Barrett T. Mutation analysis and preliminary genotype/phenotype analysis in 19 Wolfram syndrome (DIDMOAD) kindreds (Am J Hum Genet 1999;65:1279-1290)

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HNF1B MODY and RCAD syndrome

Pathogenic variants and deletions of the HNF1B gene result in a number of different clinical features.  The most commonly occurring conditions are renal abnormalities (renal cysts or renal structural abnormalities) and a form of diabetes known as Maturity-Onset Diabetes of the Young (MODY).  The combination of renal cysts and diabetes due to HNF1B is known as the Renal Cysts and Diabetes (RCAD) syndrome.

HNF1B and RCAD Information

Aniridia and diabetes (PAX6)

Heterozygous disease-causing variants in PAX6 cause aniridia (the absence of the iris) and diabetes. Other eye abnormalities have also been reported in some patients.

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Autosomal recessive juvenile-onset diabetes with microcephaly, epilepsy and intellectual disability (PPP1R15B and TRMT10A)

Recessively inherited disease-causing variants in PPP1R15B and TRMT10A cause a syndrome that can include diabetes, dysmorphic features and developmental delay as well as other features.

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Woodhouse Sakati syndrome (DCAF17)

Recessively inherited disease-causing variants in DCAF17 cause Woodhouse Sakati syndrome, a syndrome that includes hypogonadism, partial alopecia, diabetes, intellectual disability and deafness.

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Primrose syndrome  (ZBTB20)

Heterozygous disease-causing variants in ZBTB20 cause primrose syndrome which is characterized by macrocephaly, intellectual disability, dysmorphic facial features, ectopic calcifications, large calcified ear auricles, diabetes and progressive muscle wasting.

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Juvenile-onset diabetes with central and peripheral neurodegeneration (DNAJC3)

Recessively inherited disease-causing variants in DNAJC3 cause a syndrome characterised by ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus.

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Diabetes and metabolic syndrome  (DYRK1B)                 

Heterozygous disease-causing variants in DYRK1B cause a syndrome characterised by central obesity, type 2 diabetes, hypertension, and early-onset coronary artery disease.

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Diabetes and SHORT syndrome (PIK3R1)

Heterozygous disease-causing variants in PIK3R1 cause SHORT syndrome which is characterised by short stature, hyperextensibility, teething delay, insulin resistant diabetes, partial lipodystrophy and dysmorphic features.

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NGS Testing

H syndrome  (SLC29A3)

Recessively inherited disease-causing variants in SLC29A3 cause H syndrome, characterised by histiocytic disorders, diabetes and dysmorphic features.

OMIM

NGS Testing