CASE REPORT Open Access

Natural history of ROHHAD syndrome:development of severe insulin resistanceand fatty liver disease over timeAbdel Wahab Jalal Eldin1†, Dilara Tombayoglu1,2†, Laura Butz1, Alison Affinati1, Rasimcan Meral1,Mehmet Selman Ontan1, Kelly Walkovich3, Maria Westerhoff4, Jeffrey W. Innis5, Neehar D. Parikh6 andElif A. Oral1*

Absract

Background: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation(ROHHAD) is a rare syndrome with unknown etiology. Metabolic abnormalities are not known to be part of thesyndrome. We present one of the oldest cases reported in the literature, who developed severe metabolicabnormalities and hepatic disease suggesting that these features may be part of the syndrome.

Case presentation: A 27-year-old woman, diagnosed with ROHHAD syndrome at age 15, who previously developeddiabetes insipidus, growth hormone deficiency, hyperprolactinemia, and hypothyroidism in her first decade of life. Thiswas followed by insulin resistance, NAFLD, liver fibrosis, and splenomegaly before age 14 years. Her regimen included ashort course of growth hormone, and cyclic estrogen and progesterone. Her metabolic deterioration continueddespite treatment with metformin. Interestingly, she had a favorable response to liraglutide therapy despite having acentrally mediated cause for her obesity. At age 26, a 1.6 cm lesion was found incidentally in her liver. Liver biopsyshowed hepatocellular carcinoma which was successfully treated with radiofrequency ablation.

Conclusion: Metabolic abnormalities, Insulin resistance and fatty liver disease are potentially part of the ROHHADsyndrome that may develop over time. GLP1 agonists were reasonably effective to treat insulin resistance andhyperphagia. Patients with ROHHAD may benefit from close follow up in regards to liver disease.

Keywords: ROHHAD, Insulin resistance, GLP-1 agonists, Obesity, Atypical diabetes

Rapid-onset obesity with hypothalamic dysfunction,hypoventilation, and autonomic dysregulation (ROHHAD)is a rare syndrome characterized by hyperphagia and rapid-onset weight gain that starts in early childhood. The rapidweight gain is followed by hypothalamic manifestationswith neuroendocrine deficiencies, hypoventilatory breathingabnormalities, and autonomic dysregulation [1]. A geneticbasis for ROHHAD has not been established, which differ-entiates it from central hypoventilation syndrome causedby mutations in the PHOX2B gene [2]. Natural history

information about this rare syndrome is sparse, as the re-ported mortality rates are high at 50 to 60% [3] within ashort period of time after diagnosis, usually due tohypoventilation, cardiopulmonary failure or both [4–6].We have followed an unusual case of ROHHAD

syndrome for two decades, currently age 27 years, and isbelieved to be one of the oldest patients with ROHHADsyndrome. Over time, she developed novel clinical fea-tures not previously associated with ROHHAD, such assevere insulin resistance and diabetes mellitus, severehypertriglyceridemia, progressive fatty liver disease, andmore recently clinical cirrhosis and hepatocellular car-cinoma. The clinical management of the hyperglycemiahas been challenging due to the severe insulin resistanceand labile sodium and fluid balance.

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: eliforal@med.umich.edu†Abdel Wahab Jalal Eldin and Dilara Tombayoglu contributed equally to thiswork.1Division of Metabolism, Endocrinology and Diabetes (MEND), Department ofInternal Medicine Brehm Center for Diabetes, Michigan Medicine, Universityof Michigan, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105, USAFull list of author information is available at the end of the article

Jalal Eldin et al. Clinical Diabetes and Endocrinology (2019) 5:9 https://doi.org/10.1186/s40842-019-0082-y

MethodsCase reportThis is a report of a patient who was followed at theMichigan Medicine Pediatric Endocrinology Clinic untilage 18 years. She was also evaluated at the LurieChildren’s Hospital Autonomic Dysfunction Program atthe Lurie Children’s Hospital of Chicago at age 16 years.Subsequently, endocrine care was transitioned to theMetabolism, Endocrinology and Diabetes Clinic AtypicalDiabetes Program at Michigan Medicine. She was alsofollowed by the Medical Genetics specialty clinic at MottChildren’s Hospital of Michigan Medicine during thistime.The patient gave consent to share her case presenta-

tion in the medical literature and provided her pictures.Laboratory testing was performed using standard proce-dures at the clinical pathology laboratory of the Mich-igan Medicine. PHOX2B gene testing was performed atthe University of Chicago Genetics Laboratory andwhole exome sequencing of the patient and her parentswere performed by GeneDx (Gaithersburg, Maryland)using samples drawn in February 2017.Hormonal measurements were performed using the

standard procedures available in the clinical laboratoryat Michigan Medicine manual available at the Universityof Michigan Department of Pathology [7] and were re-ported in the medical record. All the testing that is beingreported here was accomplished during routine clinicalcare and no tests done for research purposes are beingreported.

Literature reviewA Pubmed search conducted using the terms ROHHAD,ROHHADNET and the syndrome full name, retrieved50 articles. These were reviewed and categorized in Add-itional file 1: Table S2 and further summarized after thecase presentation. Prior to the literature search, wesought to investigate the age of onset, the life span,current ages of surviving cases and the frequency ofmetabolic (glucose intolerance, insulin resistance orpresence of diabetes) as well as liver related complica-tions from the reported cases.

Case presentationA previously healthy, normally developing girl withoutfamilial obesity was evaluated at age 4 years for a suddenweight gain of 15 pounds in less than 1 year (25th to95th percentile for weight) and decreased linear growth(25th to 10th percentile for height; Fig. 1b). She dis-played no features of lipodystrophy. The medical historyof the patient revealed that she was born to non-consanguineous healthy parents with a birth weight of 4pounds 13 oz (2.14 Kg) by c-section at 37 weeks (3weeks preterm) due to pre-eclampsia. Her growth in the

first year of life included a height at the 75th percentileand weight at the 25th percentile. She never had anyconcerns about developmental delays or cognitiveimpairment. However, her parents noted fear and anx-iety about routine daily activities, entering crowdedspaces as well as decision making, starting around age 4years. Ophthalmic exam did not show any vision abnor-malities other than myopia and astigmatism. Given hermother’s history of hearing impairment, hearing test wasdone but did not show any abnormality.During the initial evaluation, her sodium was 156

mEq/L with undetectable antidiuretic hormone (ADH),consistent with diabetes insipidus and disrupted thirstregulation. She was also found to have centralhypothyroidism, elevated prolactin, and growth hormonedeficiency (Table 1). Her baseline cortisol levels werenormal to high with normal ACTH. A hypothalamictumor was suspected, but brain MRI was normal (Fig.1c). Due to the rapid weight gain, she was also workedup for Cushing’s syndrome, however, abdominal CT re-vealed no adrenal masses and overnight dexamethasonesuppression test was normal.She was originally started on subcutaneous DDAVP, and

then transitioned to intranasal spray. She was very closelymonitored with weekly blood draws, tight fluid instructionsand close weight tracking. Despite this tight monitoring,she still required hospitalizations for hypernatremia at thetime of infections. Given these difficulties, she never triedoral DDAVP. She was simultaneously treated with levothyr-oxine replacement.After age 10, she was diagnosed with nonalcoholic

fatty liver disease (NAFLD) with evidence of progressivefibrosis over time, resulting in hypersplenism and pan-cytopenia. Her liver function tests (LFTs) were noted tobe elevated starting at age 10. At age 11, she underwenta liver US showing the presence of increased fat as wellas splenomegaly. During the same period, she was notedto have autonomic dysfunction, abnormal thermoregula-tion, and profuse sweating.She was treated with growth hormone from age 10 to

age 14 years to assist with linear growth and it was dis-continued due to increased swelling and weight gain. Atage 10, she was diagnosed with sleep apnea and insulinresistance. She was started on metformin, but developedclinical diabetes by age 14. She did not achieve spontan-eous menarche despite the development of oily skin andacne and was started on female hormone replacementwith cyclic estrogen and progesterone therapy at the ageof 14.At age 15, she developed respiratory failure and shock

from an upper respiratory tract infection, requiring intub-ation, oscillator, and vasopressors. She was able to recoverafter a prolonged hospitalization. Shortly after at age 16,she underwent a thorough evaluation at the Lurie

Jalal Eldin et al. Clinical Diabetes and Endocrinology (2019) 5:9 Page 2 of 7

Children’s Hospital that documented her autonomic dys-function and hypoventilation (Additional file 1: Table S1).Management with overnight ventilator, oxygen supplemen-tation and oscillator use were recommended. Home con-tinuous overnight monitoring for oxygen saturation and

heart rate were also initiated. At that time, she underwentPHOX2B gene testing due to the presence of autonomicdysfunction and this testing was negative.Between the ages of 18–23, she was transitioned to

adult endocrine care where her diabetes control was

a

c

b

d

Fig. 1 a Photograph of the patient at age 4 (left) compared to 26 (right). b Coronal view of brain MRI with no abnormality detected c Growthcharts constructed with standard data obtained from CDC [20]. Stature (top), and weight (middle) display a drop in linear growth and significantweight gain at 4 years of age; increased linear growth upon initiation of growth hormone at age 7 with a plateau following discontinuation atage 14. BMI (bottom) has been in the obese range since age 4. d 10-day glucose tracing by insulin pump shows improvement in blood glucoseafter 8–12 h of starting GLP-1 agonist, liraglutide, on May 16

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noted to become more challenging. She was started oninsulin, with insulin requirement increasing to > 310international units (IU) while her HbA1c increased tonumbers above 9%. Poor diabetes control made manage-ment of sodium balance very difficult due to polyuriaand absence of thirst. She developed severe acanthosisnigricans and lymphedema. Her weight increased toBMI over 40 kg/m2. Over time, she was started on U500insulin. She also developed hypertriglyceridemia at thistime with the highest value at 1062mg/dL. Of note,given the hypertriglyceridemia, low adiponectin levelsand the lack of a commercial test, she was never testedfor presence of the insulin receptor auto-antibody.She was started on liraglutide 0.6 mg daily with the

hope of improving control and sparing insulin to im-prove acanthosis nigricans, hyperandrogenism, weightand fatty liver. Her insulin requirements dropped pre-cipitously to less than 30% of baseline doses within 8 to12 h of initiation (Fig. 1d). She was managed withliraglutide 1.2 mg daily on and off for about 2 years. Ini-tiation of liraglutide did not cause worsening of her dia-betes insipidus, hypernatremia, or pancytopenia. She did,however, experience worsened diarrhea due to the use ofliraglutide leading to treatment interruption. Heracanthosis nigricans, facial acne and coarsening of facialfeatures improved due to dose reduction in insulin.With increased weight gain, swelling, worsening

acanthosis nigricans, a weight reduction diet wasattempted with meal replacement and caloric restriction.She lost 15 lbs. with this attempt. At the age of 26, shewas noted to have a 1.6 cm Barcelona Clinic LiverCancer (BCLC) Stage 0 (T1N0M0 Stage 1) liver lesionon routine semi-annual liver surveillance because of the

presence of clinical cirrhosis and hypersplenism. The bi-opsy of the lesion favored the diagnosis of a well differ-entiated hepatocellular carcinoma (Fig. 2). Aradiofrequency ablation procedure for this was success-fully completed on 8/30/2018.In addition, other comorbidities that developed over

the years include cholelithiasis, chronic kidney diseasewith nephrotic range proteinuria (no biopsy performedto date to determine the underlying pathological mecha-nisms but being contemplated), hypertension, anemiaand thrombocytopenia, splenomegaly, irritable bowelsyndrome, vitamin D deficiency, and mild tricuspidregurgitation.

Results of literature reviewThe supplemental file summarizes all cases documentedin the literature. As shown, most cases were quite youngat the time of death or last encounter before the report.Table 2 summarizes basic clinical characteristics of thecases and the presence of the features related to insulinresistance. Overall, there were 117 cases reported. Insu-lin resistance were documented in only 5 patients andnone of them were older than teenage years. Fatty liverdisease or nonalcoholic steatohepatitis has not been re-ported previously. Definitive deaths of only 8 patientswere documented in the papers even though many ofthe reviews on this disease entity report a high incidenceof mortality before teenage years. Cause of death waspredominantly cardiopulmonary, but infections werealso reported to lead to death. Of note and not includedon the table, premature birth and low birth weight arenot typical features of ROHHAD.

DiscussionOur patient is one of the oldest described with ROH-HAD who has developed severe insulin resistance whileunder observation. This case expands the spectrum ofclinical findings in ROHHAD, to include severe insulinresistance progressing to diabetes mellitus with compli-cations, progressive NAFLD with hypersplenism, andcirrhosis as well as hepatocellular carcinoma.ROHHAD syndrome is a relatively novel disease. It

was first described by Fishman et al. in 1965 [8], but thesyndrome acquired the name in 2007 by Ize-Ludlow etal. when the diagnostic criteria were described [9]. Todate, more than 100 cases (n = 117) based on our review)have been reported in the literature [5]. Recently Lee etal. reported a systematic review of the reported cases in-dependent of our efforts, but this review did not focuson insulin resistance, dyslipidemia or fatty liver disease.In fact, the summary tables found in that review do notcomment specifically on any of these novel features [10].The syndrome is quite distinctive from Prader-Willi andother complex syndromes of obesity due to its sudden

Table 1 Childhood labs

Value Reference Range

IGF-1, ng/mL 41 70–288

GH stimulation testing GH undetectable at baseline and all-timepoints after stimulation with arginine andinsulin-induced hypoglycemia to 49mg/dL

Prolactin, ng/mL 50 1–17

ADH, pg/mL 1.7 < 1.7

Serum Na, meq/L 156 132–145

Morning cortisol, mcg/dL 12.7 < 20

TSH, mU/L 0.87 0.3–5.5

Free T4, ng/dL 0.99 0.73–1.79

Estradiol at age 12, pg/mL 8.0 < 10 prepubertal

FSH, mIU/L 0.2 3–26

LH, mIU/L 0.5 2–105

Abbreviations: IGF-1, insulin like growth factor-1; GH, growth hormone; TSH,thyroid stimulating hormone; LH, luteinizing hormone. A leptin level at age 22was measured at 99 ng/ml and an adiponectin level was 3 mcg/ml whichwas low

Jalal Eldin et al. Clinical Diabetes and Endocrinology (2019) 5:9 Page 4 of 7

onset acquired nature, absence of symptoms at birth,predominance of autonomic features, and respiratory ab-normalities as well as diabetes insipidus andhyperprolactinemia.The condition is characterized by high morbidity and

mortality rates [3, 11]. Forty per cent of patients werenoted to develop neural crest tumors (ganglioneuroma,

ganglioneuroblastoma); it was suggested that the acro-nym ROHHAD could be extended to ROHHADNET(ROHHAD-neuroendocrine tumors) [11]. Previouslyrecognized features of the syndrome include obesity,alveolar hypoventilation, autonomic dysregulation, sym-pathetic nervous system tumors. While at this point, wecannot rule out the existence of two separate disordersin our patient leading to a blended phenotype, we sug-gest that severe insulin resistance and progressive fattyliver disease may be features to the syndrome. We alsowant to draw attention to this case as a cause for the de-velopment of atypical diabetes. Evaluation of patientswith ROHHAD shoudl include evaluation for these po-tential complications and with time, we may learn thefrequency of these features in ROHHAD.The etiology of the syndrome is not known. Molecular

diagnostic studies including PHOX2B gene testing andwhole exome interrogation in conjunction with her par-ents did not reveal any causative genetic alterations inour patient including monogenic or syndromic obesityor known syndromes of insulin resistance (including theinsulin receptor). In 2011, Patwari et al. reported mono-zygotic twins, one of whom had ROHHAD syndromewhile the other twin did not, [12] suggesting that thedisease may not develop due to genomic changes. Eventhough there is no definitive understanding, it is

a

c

b

d

Fig. 2 a MRI abdomen showing hepatocellular carcinoma in the left lobe (BCLC stage A). b The liver mass biopsy showed a small amount offibrotic background liver. The main lesion was a well-differentiated hepatocellular neoplasm composed of sheets of lesional hepatocytes andabsence of normal portal structures. c This higher magnification of the hepatocellular neoplasm shows an unpaired artery (*) and surroundingwell-differentiated neoplastic hepatocytes. d Trichrome stain highlights cirrhotic background

Table 2 Case summary

Result

Diagnosis age, years (n = 23) 5.6 (3.1)

Age at last encounter, years (n = 25) 8.9 (4.7)

Number of cases reported 117

Females, male 15, 34

Hypercholesterolemia 4

Insulin resistance 5

Reported deaths 8

Case of death

Cardiorespiratory arrest 4

Respiratory pathology 1

Pneumonia 1

Septic shock 1

Disconnection from ventilator support 1

Data are presented as Mean (SD) or count out of 117 cases.

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postulated that ROHHAD may be an immune-mediatedcentral nervous system (CNS) disorder [6, 13–15] orepigenetic factors may have a role in the pathogenesisof the syndrome [12]. In this regard, it was interestingthat our patient did not demonstrate any laboratoryfeatures suggesting other autoimmune diseases at anypoint. Periodically performed imaging studies did notreveal any neural crest tumors to date either.Other than the well described pituitary hormonal defi-

ciencies, diabetes insipidus and hyperprolactinemia,other hormonal features of this syndrome are not de-scribed. Our patient had a high circulating leptin level.We are not sure if this can be generalized to other ROH-HAD patients. We did not study the incretin secretionor other circulating mediators of appetite control or en-ergy balance in our patient and are not aware of theseinvestigations in other patients.Our case presented several challenges and lessons to

us that are worth sharing. She was prepubertal when shepresented with the earliest signs of insulin resistance.She was treated with metformin almost immediately, butthis did not prevent the development of severe acantho-sis nigricans, oily skin, hirsutism and coarsening of fea-tures, despite the presence of central hypogonadism,suggesting that insulin resistance alone can drive theseaspects of clinical presentation without any centralstimulation of the pituitary. She was treated with cyclicestrogen and progesterone replacement for bone health.Our patient was also treated with growth hormone forseveral years to assist with linear growth, but this waskept short due to worsening weight gain and swelling.Management of her case from childhood through earlyadulthood remained quite complicated and she requiredfrequent lab monitoring and clinical visits. Both her par-ents and herself remained very vigilant about her care.Long term survivors with this syndrome need to beclosely monitored and care transitions from pediatric toadult endocrinology should be undertaken in a plannedmanner.Insulin resistance and adult growth hormone defi-

ciency are associated with non-alcoholic fatty liverdisease (NAFLD) and non-alcoholic steatohepatosis(NASH); the latter can progress to liver cirrhosis and he-patocellular carcinoma in some cases [16]. High doses ofinsulin, growth hormone, and even estrogen may havealso contributed to the development of hepatocellularcancer [17]. In addition, prolactin receptors are some-times expressed in hepatocellular cancers [18] and ourpatient has had mild, but untreated hyperprolactinemiasince the onset of her condition. Our patient’s hyperpro-lactinemia was never adequately addressed; dopamineagonists were never initiated due to the presence ofautonomic dysfunction, and fear of worsening orthosta-sis. We recommend screening for hepatic lesions using

abdominal ultrasound in other patients presenting withthe clinical features of NAFLD in the setting of ROH-HAD as they grow older, particularly if they have signsof advanced hepatic fibrosis or cirrhosis. In addition,presence of clinical diabetes and insulin resistanceshould also be screened in addition to various endocrinemanifestations.The immediate improvement in glycemic control fol-

lowing liraglutide initiation indicates that the insulin re-sistance seen in this patient can be partially overcomewith glucagon-like peptide-1 (GLP-1) agonism and addsto the growing evidence that GLP-1 receptor agonistsmay exert their metabolic actions via neural circuitrylocated outside of the hypothalamus, or via peripheralmechanisms [19]. Treatment experience in a largernumber of patients is needed to validate these earlyobservations.Finally, our patient’s sodium and fluid balance man-

agement were markedly tenuous on account of poorlycontrolled diabetes, presence of diabetes insipidus andabsence of thirst regulation. The patient required weeklysodium monitoring and constant adjustment of her fluidintake recommendation and her DDAVP dose. Inter-current illnesses (such as upper respiratory tract, urinarytract infections, or cellulitis episodes) and naturaltemperature fluctuations impacted her sodium levels.Our patient had multiple hospitalizations for dehydra-tion and hypernatremia despite being compliant withinstructions and carrying out frequent laboratory testing.Ideal glucose control (also a challenging goal for this pa-tient) was essential to maintain her sodium balancecloser to the normal range.

ConclusionROHHAD is an interesting syndrome presenting with acharacteristic cluster of abnormalities. There appears to beheterogeneity among patients diagnosed with ROHHADand careful clinical characterization is required to moreprecisely define this disease entity. Our case expands on theclinical features of this syndrome to include severe and pro-gressive insulin resistance and fatty liver disease. It shouldbe noted that the fatty liver disease in this condition can beaggressive and result in development of cirrhosis that canbe complicated by hepatocellular carcinoma.

Additional file

Additional file 1: Table S1. Autonomic testing available on subject.Table S2 Summary data abstracted from reported cases and respectivereferences. (DOCX 79 kb)

AbbreviationsADH: Antidiuretic hormone; BCLC: Barcelona Clinic Liver Cancer;DDAVP: Desmopressin Acetate; GLP-1: Glucagon-like peptide 1; LFT: Liverfunction test; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic

Jalal Eldin et al. Clinical Diabetes and Endocrinology (2019) 5:9 Page 6 of 7

steatohepatosis; ROHHAD: Rapid-onset obesity with hypothalamicdysfunction, hypoventilation, and autonomic dysregulation;ROHHADNET: Rapid-onset obesity, hypothalamic dysfunction,hypoventilation, autonomic dysregulation, and neuroendocrine tumor

AcknowledgmentsWe thank the patient for giving permission to report her interesting clinicalstory and sharing her pictures. J.W.I. would like to acknowledge support fromthe Morton S. And Henrietta K. Sellner Professorship in Human Genetics.

Authors’ contributionsDr. Jalal Eldin compiled data, reviewed the literature, worked on artwork,contributed to the writing, reviewed and edited the manuscript. Dr.Tombayoglu compiled data, reviewed literature, contributed to the writing,reviewed and edited the manuscript. Dr. Laura Butz was involved in care ofthe patient, reviewed and edited the manuscript. Dr. Allison Affinati wasinvolved in the care of the patient, provided critical insight in thepathophysiology, reviewed and edited the manuscript. Dr. Rasimcan Meralhelped with artwork, and review of literature, reviewed and edited themanuscript. Dr. Mehmet Selman Ontan helped with artwork, and review ofliterature, reviewed and edited the manuscript. Dr. Kelly Walkovich wasinvolved in the care of the patient, provided critical insight in thepathophysiology, reviewed and edited the manuscript. Dr. Maria Westerhoffwas involved in the care of the patient, provided critical insight in thepathophysiology, reviewed and edited the manuscript. Dr. Jeffrey W. Inniswas involved in the care of the patient, provided critical insight in thepathophysiology, reviewed and edited the manuscript. Dr. Neehar Parikh wasinvolved in the care of the patient, provided critical insight in thepathophysiology, reviewed and edited the manuscript. Dr. Elif A. Oral,personally cared for the patient over 10 years, wrote the manuscript withhelp from Drs. Jalal Eldin and Tombayoglu, reviewed all available data andliterature, reviewed and edited the manuscript. Dr. Oral is responsible for theintegrity of the manuscript and data analyses.

FundingThere is no funding source for this case report.Dr. Oral also received grant support from and served as an advisor to AmylinPharmaceuticals LLC, Bristol-Myers-Squibb, AstraZeneca in the past. She iscurrently receiving grant support from Gemphire Therapeutics, AegerionPharmaceuticals, Ionis Pharmaceuticals and Akcea Therapeutics and servingas an advisor to Aegerion Pharmaceuticals, Akcea Therapeutics and Regen-eron Pharmaceuticals. EAO recently completed grant support from GI Dy-namics. None of these are related to the content of the paper.

Availability of data and materialsAll data analyzed during this study are included in this published article.

Ethics approval and consent to participateThere is no Ethics approval and consent to participate as this is a single casereport.

Consent for publicationPatient has given us written consent for publication.

Competing interestsThe authors declare that they have no competing interests.

Author details1Division of Metabolism, Endocrinology and Diabetes (MEND), Department ofInternal Medicine Brehm Center for Diabetes, Michigan Medicine, Universityof Michigan, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105, USA.2Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 3Divisionof Pediatric Hematology/Oncology, Department of Pediatrics andCommunicable Diseases, Michigan Medicine, University of Michigan, AnnArbor, MI, USA. 4Department of Pathology, Michigan Medicine, University ofMichigan, Ann Arbor, MI, USA. 5Division of Genetics, Metabolism andGenomic Medicine, Department of Pediatrics,and Departments of HumanGenetics and Internal Medicine, Michigan Medicine, University of Michigan,Ann Arbor, MI, USA. 6Division of Gastroenterology and Hepatology,Department of Internal Medicine, Michigan Medicine, University of Michigan,Ann Arbor, MI, USA.

Received: 4 February 2019 Accepted: 24 June 2019

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