Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Ethical considerations of maternal-fetal surgery.

The practice of maternal-fetal surgery (MFS) has expanded from lethal fetal conditions to conditions which are significantly disabling but not a lethal fetal abnormality. The inclusion of myelomeningocele within the scope of MFS in the 1990s sparked a renewed debate over the ethics of MFS. While demonstrating increasing efficacy and range of application, MFS continues to be ethically fraught due to the inherent tension between maternal and fetal interests. Ethical issues central to MFS include the patienthood of the fetus; the balance of risks and benefits between the woman and fetus; informed consent for experimental procedures; and determination of conditions that meet ethical qualifications for MFS intervention. These concerns are likely to persist and evolve as perinatal medicine continues to advance. Here we summarize the current state of MFS ethics, highlighting the major positions in the literature thus far as well as examine future directions. It is essential robust discussions of these important issues continue both to ensure ethical medical practice and to provide support to clinicians, pregnant women, and their families.

Consult and procedure incidence outcomes following establishment of a fertility preservation program for children with cancer.

PURPOSE: Fertility is a quality of life outcome adversely affected by cancer therapy. Many childhood cancer patients, however, are not offered options to preserve their fertility. Providers acknowledge difficulty discussing impaired fertility to patients due to lack of knowledge of available options. Our objective was to review the impact of a pediatric multidisciplinary fertility preservation program on providers' fertility preservation counseling and discussion of options. METHODS: A retrospective medical chart review was conducted for pediatric cancer patients prior to and following program establishment. Fertility preservation discussions, consults, and incidence were noted. Following filtering and stratification, 198 and 237 patients were seen prior to and following program establishment, respectively. RESULTS: Following program establishment, provider-patient discussions of impaired fertility (p = 0.007), fertility preservation consults (p = 0.01), and incidence of fertility preservation procedures (p < 0.001) increased among patients. Furthermore, the number of patients who received fertility preservation consults after receiving gonadotoxic treatment decreased (p < 0.001). This trend was particularly noted in pre-pubertal and female patients, for whom fertility preservation options are limited without an established program. CONCLUSION: The establishment of a formal program greatly improved access to fertility preservation consults and procedures in children with cancer.

Diagnostic accuracy of the McGill thyroid nodule score in paediatric patients.

INTRODUCTION: Thyroid cancer is the most common paediatric endocrine cancer; accurate diagnosis and prompt management of paediatric thyroid nodules is critical. The McGill Thyroid Nodule Score (MTNS), based upon clinical, ultrasound (US) and cytology criteria, has recently been modified and studied in a pilot paediatric group with good results. We aim to describe the diagnostic accuracy of the paediatric modified MTNS (PMTNS) in a large paediatric cohort. METHODS: We utilized an established retrospective cohort between 1996 and 2015 of 99 patients ≤21 years old with 131 thyroid nodules. Two experienced paediatric radiologists, blinded to pathology and radiology reports, reviewed US features. We abstracted cytology, histology and laboratory results, assigning each nodule a PMTNS. PMTNS performance was compared to FNA and histology. RESULTS: Approximately 33% of nodules were malignant. The cohort was predominantly adolescent (mean age 15.4 ± 3.8 years). The average PMTNS for malignant and benign nodules, based on final histology, was 12.7 ± 4.3 and 1.7 ± 2.9, respectively. A PMTNS ≥8 resulted in a 93.2% sensitivity and 93.1% specificity for detecting malignancy, while a PMTNS ≥9 resulted in a 90.9% sensitivity and 96.6% specificity. However, Bethesda cytology category ≥4 independently had a 97.7% sensitivity and 94.0% specificity for detecting malignancy. The PMTNS had diminishing diagnostic accuracy in younger children compared with older children. CONCLUSION: Paediatric modified McGill Thyroid Nodule Score predicts malignancy, perhaps due to the score's emphasis on cytology results; however, the score is less accurate in younger patients. While cytology results remain reliable, further work is needed to develop a non-invasive scoring system to predict malignancy in children.

Mild subclinical hypothyroidism is associated with paediatric dyslipidaemia.

BACKGROUND: There is a lack of consensus on the cardiometabolic consequences of mild subclinical hypothyroidism (SCH) among children. The objective of the current study was to compare lipid profiles in children with mild SCH with those of euthyroid children. STUDY DESIGN: Retrospective medical record review. PATIENTS: Children (ages 2-18 years) who had undergone simultaneous measurement of TSH, free thyroxine (T4) and lipids. Lipids in children with mild SCH (TSH 5-<10 mIU/L and normal free T4, n = 228) were compared with those in euthyroid children (n = 1215). RESULTS: TSH level was positively associated with total cholesterol and nonhigh density lipoprotein (non-HDL) cholesterol [ß 0.05(0.03-0.08), P < .0001 and ß 0.05(0.03-0.08), P < .0001, respectively]. Total cholesterol was significantly higher in children and adolescents with mild SCH compared with euthyroid children (4.43 ± 1.14 mmol/L vs 4.2 ± 0.85 mmol/L, P = .0005). Similarly, non-HDL cholesterol level was also higher in children with mild SCH relative to euthyroid children (3.08 ± 1.14 mmol/L vs 2.91 ± 0.8 mmol/L, P = .001). The adjusted odds ratio of having elevated total cholesterol and elevated non-HDL cholesterol was greater in children with mild SCH compared with euthyroid children (OR 1.88, 95% CI; 1.28-2.73; P = .001 and 1.72, 95% CI 1.2-2.5; P = .003, respectively). The presence of thyroid autoimmunity was not associated with higher rates of dyslipidaemia. CONCLUSIONS: Mild SCH in children and adolescents was associated with higher rates of elevated total cholesterol and elevated non-HDL cholesterol. Randomized placebo controlled studies are warranted to determine if treatment of mild SCH in children leads to improvement in lipid profile.

Papillary Thyroid Carcinoma (PTC) in Children and Adults: Comparison of Initial Presentation and Long-Term Postoperative Outcome in 4432 Patients Consecutively Treated at the Mayo Clinic During Eight Decades (1936-2015).

BACKGROUND: Contemporary guidelines for managing PTC advise an approach wherein primary tumor and regional metastases (RM) are completely resected at first surgery and radioiodine remnant ablation (RRA) is restricted to high-risk patients, policies our group has long endorsed. To assess our therapeutic efficacy, we studied 190 children and 4242 adults consecutively treated during 1936-2015. SUBJECTS AND METHODS: Mean follow-up durations for children and adults were 26.9 and 15.2 years, respectively. Bilateral lobar resection was performed in 86% of children and 88% of adults, followed by RRA in 30% of children and 29% of adults; neck nodes were excised in 86% of children and 66% of adults. Tumor recurrence (TR) and cause-specific mortality (CSM) details were taken from a computerized database. RESULTS: Children, when compared to adults, had larger primary tumors which more often were grossly invasive and incompletely resected. At presentation, children, as compared to adults, had more RM and distant metastases (DM). Thirty-year TR rates were no different in children than adults at any site. Thirty-year CSM rates were lower in children than adults (1.1 vs. 4.9%; p = 0.01). Comparing 1936-1975 (THEN) with 1976-2015 (NOW), 30-year CSM rates were similar in MACIS <6 children (p = 0.67) and adults (p = 0.08). However, MACIS <6 children and adults in 1976-2015 had significantly higher recurrence at local and regional, but not at distant, sites. MACIS 6+ adults, NOW, compared to THEN, had lower 30-year CSM rates (30 vs. 47%; p < 0.001), unassociated with decreased TR at any site. CONCLUSIONS: Children, despite presenting with more extensive PTC when compared to adults, have postoperative recurrences at similar frequency, typically coexist with DM and die of PTC less often. Since 1976, both children and adults with MACIS <6 PTC have a <1% chance at 30 years of CSM; adults with higher MACIS scores (6 or more) have a 30-year CSM rate of 30%.

Options for Fertility Preservation in Children.

Fertility preservation therapies can conserve future reproductive potential for persons facing serious medical diagnoses. With cure rates for childhood cancer reaching almost 80%, quality-of-life concerns for long-term survivors, including future parenting, are becoming more pertinent. Late effects of childhood cancer can be divided into physical, social, psychological, and spiritual domains. Potential loss of fertility threatens the well-being of these children in all these domains. Providers often hesitate to discuss fertility preservation with the patients. However, parental attitudes toward discussion of fertility preservation have been found to be open to such conversations for both prepubertal and postpubertal children who have a cancer diagnosis. Multiple national and international organizations recommend discussion with all persons having gonadotoxic therapy, including children, regarding the effect of planned treatment on future fertility and their options for fertility preservation. Renal or rheumatologic disease treated with high-dose cyclophosphamide and chromosomal anomalies such as Turner or Klinefelter syndrome may be amenable to fertility preservation. This essay reviews fertility preservation options available to children, as well as the expanding list of indications for fertility preservation.

Accuracy of thyroid nodule sonography for the detection of thyroid cancer in children: systematic review and meta-analysis.

INTRODUCTION: Thyroid ultrasound (US) is a widely used tool for evaluating thyroid nodules. Various US features have been suggested as predictors of thyroid cancer in children. OBJECTIVE: To conduct a systematic review and meta-analysis to assess the diagnostic accuracy of different thyroid US features in detecting thyroid cancer in children. METHODS: We searched multiple online databases for cohort studies that enrolled paediatric patients with thyroid nodules (age <21 years) and evaluated the accuracy of 12 relevant ultrasound features. Diagnostic measures were pooled across studies using a random effects model. RESULTS: The search strategy yielded 1199 citations, of which 12 studies met the predefined inclusion criteria (750 nodules). The prevalence of thyroid cancer was 27·2% (40·8% in patients with a history of radiation exposure and 23·2% in patients without a history of exposure to radiation). The most common cancer was papillary thyroid cancer (86·7%). The presence of internal calcifications and enlarged cervical lymph nodes were the US features with the highest likelihood ratio [4·46 (95% CI: 1·87-10·64) and 4·96 (95% CI: 2·01-12·24), respectively] for thyroid cancer. A cystic nodule was the feature with highest likelihood ratio for benign nodules [1·96 (95% CI: 0·87-4·43)]. CONCLUSION: Thyroid US features are not highly accurate predictors of benign or malignant aetiology of thyroid nodules in children. Internal calcification may predict malignancy, and cystic appearance may suggest benign aetiology.

The relation of peripubertal and pubertal growth to final adult height in children with classic congenital adrenal hyperplasia.

OBJECTIVES: To determine the relationships between peripubertal and pubertal timing and growth, along with glucocorticoid exposure, to the reduced final adult height seen in patients with congenital adrenal hyperplasia (CAH). STUDY DESIGN: Chart review of 104 children with classic CAH (41 males: 28 salt-wasting, 13 simple-virilizing; 63 females: 38 salt-wasting, 25 simple-virilizing) were selected from a cohort from 3 medical institutions in Minnesota. Triple logistic modeling of longitudinal data was performed to determine patterns of peripubertal and pubertal growth. RESULTS: Hydrocortisone dose was similar between subtypes and during all growth periods. Simple-virilizing boys (P < .01) and girls (P < .01) were diagnosed later than their salt-wasting counterparts. Height at take-off SDS was reduced for patients with salt-wasting (boys: P < .01; girls: P < .01), and bone age at take-off SDS was more advanced for patients with simple-virilizing (boys: P < .01; girls: P = .05). Bone age at pubertal onset SDS was advanced for all patients, but more so for boys and girls with simple-virilizing. Although all patients had reduced final adult height SDS, this was more pronounced in patients with salt-wasting. CONCLUSION: Reduced final adult height SDS in patients with salt-wasting vs simple-virilizing may be attributable in part to a later age of diagnosis and resultant less prolonged exposure to hydrocortisone. This finding suggests that duration of hydrocortisone treatment in the peripubertal period, independent of the hydrocortisone dose, may affect final adult height in patients with CAH.

Impact of hydrocortisone on adult height in congenital adrenal hyperplasia-the Minnesota cohort.

OBJECTIVE: To estimate the impact of the average daily dose of hydrocortisone (HC) on the amount of growth attained in children with congenital adrenal hyperplasia (CAH). The effect of glucocorticoid therapy on adult height (AH) in children with CAH has yet to be elucidated. STUDY DESIGN: Triple-logistic models estimating components of growth and maturation were fitted to longitudinal records of 104 patients with classic CAH from 3 pediatric medical centers in Minnesota between 1955 and 2012. A total of 3664 clinical encounters were examined. Random-effects longitudinal models with time-related covariates were used to estimate the effect of HC therapy on linear growth. RESULTS: The predicted AH z-score (-0.7) was similar between the sexes and among CAH subtypes. The mean growth period HC dose was 18.9 ± 5.6 mg/m(2)/day. In the final regression model, HC dose was negatively associated with predicted AH, with each mg/m(2)/day increase in average growth period HC dose predicting a 0.37-cm decrease in AH (P < .004). CONCLUSION: This study has quantified the fractional reduction in predicted final AH with an incremental increase in HC dose. These findings have important clinical implications in the decision making balance between HC replacement dose and adrenal androgen suppression in children with CAH.

Clinical Utility and Outcome Prediction of Early ZnT8-IgG Testing and Titer in Type 1 Diabetes

Objective: Type 1 diabetes autoantibodies are directed against multiple antigens including: glutamic acid decarboxylase, protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence or titer of ZnT8 antibodies (Ab) was predictive for clinical presentation at diagnosis or for the subsequent disease course. Methods: Between January, 2003 and May, 2019, 105 patients aged ≤21 years with a clinical diagnosis of type 1 diabetes mellitus had at least 1 autoantibody measured. A retrospective chart review was completed. At diagnosis, we evaluated the body mass index z-score, hemoglobin (HbA1c), and the presence of diabetic ketoacidosis (DKA). Complications analyzed post-diagnosis included episodes of DKA, the diagnosis of autoimmune disease, and the presence of vascular complications. We evaluated cumulative lifetime excess glucose as HbA1c area under the curve (AUC) >6%. Results: Seventy-one patients were ZnT8-Ab(+) (68%), with 19 having low titer ZnT8-Ab and 52 with high titer ZnT8-Ab. Follow-up ranged from 10 days to 15.7 years (median 2.08 years). There were no differences in the characteristics at disease onset or in the subsequent follow-up between those with and those without ZnT8-Ab or those with high or low titers of ZnT8 Ab, except for a small but statistically significant difference in cumulative excess glucose (HbA1c AUC >6%) between those with low and high titers (p=0.0095). Conclusion: Our study adds to the limited literature on the effect of the presence and titer of ZnT8-Ab in pediatric diabetes. The small effect of ZnT8-Ab titer on glucose excess as measured by HbA1c AUC warrants further study.

Exogenous Insulin Antibody Syndrome in a Pediatric Patient: Successful Treatment with Mycophenolate Mofetil.

INTRODUCTION: Exogenous insulin antibody syndrome (EIAS) rarely occurs in type 1 diabetes and should be considered in those with blood glucose levels outside the target range requiring greater than 2 units/kg/day of insulin without obesity. We describe the novel treatment of this condition using mycophenolate mofetil monotherapy in a pediatric patient in the outpatient setting. CASE PRESENTATION: A 17-year-old Caucasian male with type 1 diabetes experienced an abrupt increase in insulin requirements from 1.7 to 3.3 units/kg/day. Total insulin level was 7 µIU/mL with free insulin of 4.8 µIU/mL (68% of the total insulin), suggesting the presence of insulin antibodies. Switching from insulin aspart to glulisine was unsuccessful as insulin requirements increased to 4.4 units/kg/day. Treatment with oral mycophenolate mofetil decreased insulin requirements to 1.4 units/kg/day after 7 months. Total and free insulin levels improved to 5.2 and 4.6 µIU/mL, respectively (free insulin was 88% of total insulin). No adverse effects were encountered. CONCLUSION: Mycophenolate mofetil monotherapy is successful in safely treating EIAS in a pediatric patient.

Long-term Effectiveness of Ethanol Ablation in Controlling Neck Nodal Metastases in Childhood Papillary Thyroid Cancer.

Context: Childhood papillary thyroid carcinoma (CPTC), despite bilateral thyroidectomy, nodal dissection and radioiodine remnant ablation (RRA), recurs within neck nodal metastases (NNM) in 33% within 20 postoperative years. These NNM are usually treated with reoperation or further radioiodine. Ethanol ablation (EA) may be considered when numbers of NNM are limited. Objective: We studied the long-term results of EA in 14 patients presenting with CPTC during 1978 to 2013 and having EA for NNM during 2000 to 2018. Methods: Cytologic diagnoses of 20 NNM (median diameter 9 mm; median volume 203 mm3) were biopsy proven. EA was performed during 2 outpatient sessions under local anesthesia; total volume injected ranged from 0.1 to 2.8 cc (median 0.7). All were followed regularly by sonography and underwent volume recalculation and intranodal Doppler flow measurements. Successful ablation required reduction both in NNM volume and vascularity. Results: Post EA, patients were followed for 5 to 20 years (median 16). There were no complications, including postprocedure hoarseness. All 20 NNM shrank (mean by 87%) and Doppler flow eliminated in 19 of 20. After EA, 11 NNM (55%) disappeared on sonography; 8 of 11 before 20 months. Nine ablated foci were still identifiable after a median of 147 months; only one identifiable 5-mm NNM retained flow. Median serum Tg post EA was 0.6 ng/mL. Only one patient had an increase in Tg attributed to lung metastases. Conclusion: EA of NNM in CPTC is effective and safe. Our results suggest that for CPTC patients who do not wish further surgery and are uncomfortable with active surveillance of NNM, EA represents a minimally invasive outpatient management option.

Copeptin levels in hospitalized infants and children with suspected vasopressin-dependent disorders: a case series.

OBJECTIVES: There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia. METHODS: We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021. RESULTS: A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L. CONCLUSIONS: While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.

Comprehensive Diabetes Autoantibody Laboratory-Based Clinical Service Testing in 6044 Consecutive Patients: Analysis of Age and Sex Effects.

BACKGROUND: In 2017, Mayo Clinic Laboratories commenced offering a comprehensive type 1 diabetes mellitus (T1DM) autoantibody (Ab) evaluation including 4 known Abs targeting glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and zinc transporter 8 protein (ZnT8) antigens. METHODS: The objective of this study was to evaluate real-time data on the frequency and patterns of all 4 Abs stratified by age and sex from 6044 unique consecutive adult and pediatric patients undergoing evaluation for suspected diabetes. RESULTS: At least one Ab was found in 3370 (56%) of all samples: 67% of children (aged 0-17), 49% of young adults (aged 18-35), and 41% for both middle-aged (aged 36-55) and older (aged >55) adults (P ≤ 0.0001). GAD65-Abs were the most common in all age groups, followed by ZnT8-Ab in those <36 years, or IAA-Ab in those ≥36. Frequencies of IA2- and ZnT8-Abs drop significantly with increasing age. Clusters of 3 or 4 Abs were more frequently encountered in younger patients (41% of children vs 12% in middle- and 13% in older age groups, P ≤ 0.0001). CONCLUSIONS: Children undergoing serological evaluation for T1DM were more commonly positive for autoantibodies than older age groups. The frequency of ZnT8- and IA2-Abs decreases, and IAA-Ab frequency increases with increasing age, and clusters of 2 to 4 autoantibodies are more common in children. In clinical practice, comprehensive testing for diabetes autoantibodies resulted in a switch in diagnosis to T1DM for patients previously classified as type 2 diabetes mellitus.

Ethical considerations of maternal-fetal intervention in a twin pregnancy discordant for anomalies.

BACKGROUND: Recent evidence suggests prenatal fetoscopic tracheal occlusion (FETO) may improve the survival and long-term morbidity of neonates with congenital diaphragmatic hernia, yet little guidance exists in the medical literature as to the ethical permissibility of performing a maternal-fetal surgical intervention in a twin pregnancy discordant for a structural abnormality. CASE: Here, we present a case of a twin pregnancy with an unaffected twin (Twin A) and a twin diagnosed with severe congenital diaphragmatic hernia (Twin B). A proposed fetoscopic tracheal occlusion (FETO) procedure may improve the likelihood of survival and postnatal outcome of Twin B; however, balloon placement may also initiate very preterm birth at 28 weeks of gestation. The Fetal Ethics Advisory Board was asked to provide guidance on the permissibility of FETO in this pregnancy. DISCUSSION: A literature review identified one brief mention of FETO in a 34-week dichorionic twin pregnancy in the medical literature, which resulted in the rupture of fetal membranes in the sac of the nonsurgical twin. Only one paper specifically addressed the question of whether it would be ethically permissible to subject a healthy twin to the risks of maternal-fetal surgery for the benefit of a compromised twin, finding that any risk to the unaffected twin would be an ethical contraindication. We offer our own analysis of moral weight and risk/benefit considerations of this proposed intervention, and present our findings on the circumstances in which it may be ethically permissible to perform a maternal-fetal intervention in a twin pregnancy. CONCLUSION: While FETO was not ethically advisable in this pregnancy, we find that in limited circumstances, certain maternal-fetal surgical interventions may be ethically permissible in a twin pregnancy discordant for a structural abnormality if the risks to the unaffected twin are minimal and the procedure would improve the likelihood of survival and postnatal outcome of a critically compromised co-twin.

Liver Transplantation and Development of Diabetes in an Adolescent Male With HNF1B Disease.

Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene cause a variety of diseases in different organ systems. Mutations have been described as causing neonatal cholestasis, maturity-onset diabetes of the young (type 5), cortical renal cysts, urogenital abnormalities, liver dysfunction, and atrophy of the pancreas. We describe a male patient who presented with cholestatic liver disease in infancy which progressed by age 14 to end-stage liver disease due to HNF1B disease. He subsequently underwent liver transplantation at age 15 and then developed diabetes requiring insulin which did not resolve after cessation of corticosteroids. To our knowledge, this is the first case reported of liver transplantation for decompensated cirrhosis secondary to HNF1B disease.