{"id":9437,"date":"2026-01-24T08:35:20","date_gmt":"2026-01-24T08:35:20","guid":{"rendered":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/family-history-in-the-diagnosis-of-monogenic-diabetes-leads-and-misleads\/"},"modified":"2026-01-24T08:35:20","modified_gmt":"2026-01-24T08:35:20","slug":"family-history-in-the-diagnosis-of-monogenic-diabetes-leads-and-misleads","status":"publish","type":"post","link":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/family-history-in-the-diagnosis-of-monogenic-diabetes-leads-and-misleads\/","title":{"rendered":"Family history in the diagnosis of monogenic diabetes \u201cleads and misleads\u201d"},"content":{"rendered":"
Cristina Colom,1<\/sup> Josep Oriola,2<\/sup> Silvia Mart\u00ednez,3<\/sup> Francisco Blanco-Vaca,4<\/sup> Roser Casamitjana,2<\/sup> Rosa Corcoy1,5<\/sup> <\/div>\n
1<\/sup>Servei d\u2019 Endocrinologia i Nutrici\u03cc, Hospital de la Santa Creu i Sant Pau, 2<\/sup>Servei de Bioqu\u03afmica i Gen\u00e8tica Molecular (CDB), Institut d\u2019 Investigacions Biom\u00e8diques August Pi i Sunyer, Hospital Cl\u03afnic i Universitari, 3<\/sup>Servei de Bioqu\u03afmica Cl\u03afnica, Hospital de la Santa Creu i Sant Pau, Barcelona, 4<\/sup>Servei de Bioqu\u03afmica Cl\u03afnica, Hospital de la Santa Creu i Sant Pau, Barcelona; Departament de Bioqu\u03afmica i Biologia Molecular, Universitat Aut\u00f2noma de Barcelona; CIBERDEM, Instituto de Salud Carlos III, Madrid, 5<\/sup>Departament de Medicina, Universitat Aut\u00f2noma de Barcelona; CIBER Bioengineering, Biomaterials and Nanotechnology, Instituto de Salud Carlos III, Madrid, Spain <\/div>\n
\n

Abstract<\/h2>\n

Always granting that de novo mutations are possible, family history and biological characteristics are nonetheless crucial for the diagnosis of monogenic diabetes. We report here the case of two patients with monogenic diabetes in which the initial family history misled the diagnostic work-up and did not support the diagnosis. Family history details changed substantially after the molecular diagnosis was established. <\/p><\/div>\n

\n

INTRODUCTION <\/span><\/p>\n

Any medical history should include family history given that in many diseases there is a genetic component and in some cases inheritance is crucial. In diabetes mellitus (DM), a family history with many affected members usually points to the diagnosis of Type 2 DM (T2DM). The concordance of T2DM in monozygotic twins is 60-90%, and in first-degree relatives of patients with T2DM, the risk of impaired glucose tolerance increases more than 5-fold.1<\/sup> In type 1 diabetes (T1DM) the risk of inheritance is lower, with a concordance of 30% in monozygotic twins and a disease risk in first-degree relatives of 5-10%.2-4<\/sup> However, when the inheritance pattern is autosomal dominant and the patient has neither have autoimmunity against the beta-cell or a metabolic syndrome phenotype, it is compelling to consider the possibility of monogenic DM due to defects in the beta cell. Monogenic DM represents 1-2% of DM in Europe.5,6<\/sup> In the diagnosis of monogenic DM, the family tree is important since the characteristics of other family members can help to identify the affected gene and reduce the cost of diagnosis.7<\/sup> Thus, it is important that family history is correct. We report on two patients with monogenic DM in whom where initial history was misleading because it was incorrect, despite being taken from well-educated subjects enjoying good family relationships.<\/p>\n

PATIENT 1 <\/span><\/p>\n

A 33-year old man diagnosed with DM when he was 14 after detection of simple hyperglycaemia. He came to the outpatient consultation, having been referred by his partner (health professional). His family history is summarized in Figure 1.<\/p>\n

<\/p>\n

Figure 1.<\/span> Family history of diabetes mellitus in patient 1 at consultation. Filled forms indicate family members with diabetes. y: years; DM: diabetes mellitus; Tx: treatment; OA: oral agents; Dx: diagnosis; FPG: fasting plasma glucoses; N: Normal; GDM: gestational diabetes mellitus: GCK: glucokinase. After diagnosis of the index case, GCK mutation was confirmed in all affected individuals and birth weight figures were modified to 3650 and 4259 g respectively. <\/p>\n

The patient had normal weight (BMI 21 kg\/m2<\/sup>) and reported fasting plasma glucose figures between 6.7-7.2 mmol\/l in the absence of drug treatment. Additional work-up: glycated haemoglobin (HbA1c) 6.6% (49 mmol\/mol) (reference values 4.6 – 5.8%; 27-40 mmol\/mol), negative antiGAD antibodies, C peptide in the low normal range (348 pmol\/l, reference values 298-1324 pmol\/l) coinciding with fasting plasma glucose in the diabetic range (7.3 mmol\/l).<\/p>\n

The family history was consistent with monogenic DM (autosomal dominant inheritance pattern and diagnosis before 25 years in two members).7<\/sup> Mild hyperglycaemia in all affected members and absence of complications after long duration of DM suggested glucokinase (GCK<\/em>) deficiency. However, the remarkably high birth weight of the index case and his brother was not typical of GCK<\/em> deficiency where a normal or low birth weight of affected subjects (depending on the presence or absence of maternal DM) is characteristic.8<\/sup> In the genetic work-up (guided by the frank macrosomia in the two brothers) the first studied gene was HNF4A.<\/em>9<\/sup> Subsequently, HNF1A<\/em> and GCK<\/em> genes were analyzed and a heterozygous mutation was detected in the latter (c.1183G>T; p.Glu395X) in exon 9. The mutation is an already described stop-codon mutation in a highly conserved region. On our obtaining the results of the genetic study, the patient was questioned again about his birth weight and that of his brother. After asking his mother, he reported that birth weights were 3650 g and 4259 g respectively. All the family members with diabetes were found to have the mutation.<\/p>\n

PATIENT 2 <\/span><\/p>\n

A 32-year old woman (healthcare professional) who consulted for pregnancy planning. She had been diagnosed with T1DM at 19 years of age (simple hyperglycaemia, HbA1c 19.5% (194 mmol\/l), negative antiGAD antibodies). She was receiving insulin treatment with a bolus-basal schema resulting in acceptable glycaemic control. She did not have diabetic complications, either late or acute. She had also been diagnosed of a hypoplastic kidney and mild renal failure. During follow-up the patient became pregnant three times while sustaining in acceptable glycaemic control (first HbA1c in pregnancy ranging from 5.3% (34 mmol\/mol) to 6.1% (43 mmol\/mol) and she had three spontaneous miscarriages. The infertility study detected a bicornuate uterus.<\/p>\n

The extrapancreatic manifestations of the patient suggested a monogenic DM due to a mutation in HNF1B<\/em> despite the absence of a suggestive family history (Figure 2).10-12<\/sup><\/p>\n

<\/p>\n

Figure 2.<\/span> Family history of diabetes mellitus in patient 2 before genetic diagnosis. Filled forms indicate family members with diabetes. y: years, DM: diabetes mellitus; Tx: treatment; OA: oral agents, dx: diagnosis, T1DM: diabetes mellitus type 1. <\/p>\n

<\/p>\n

Figure 3.<\/span> Family history of diabetes mellitus in patient 2 after diagnosis of HNF1B deletion. Filled forms indicate family members with diabetes.y: years, DM: diabetes mellitus; Tx: treatment; OA: oral agents, dx: diagnosis, IFG: impaired fasting glucose, T1DM: diabetes mellitus type 1; HNF1B: hepatic nuclear factor 1\u00df.
<\/sup><\/p>\n

The genetic study demonstrated a whole HNF1B<\/em> gene deletion. During the consultation, after being informed of the diagnosis, the patient expanded on the family history details (Figure 3), now including DM with an autosomal dominant inheritance pattern and kidney disease in an uncle.<\/p>\n

Molecular diagnosis was not performed in family members after diagnosis of index case.<\/p>\n

DISCUSSION <\/span><\/p>\n

Usual indications for the diagnosis of monogenic DM are the presence of a consistent family history, absent features of metabolic syndrome, one or more members diagnosed before 25 years of age, lack of autoimmunity against the beta cell and relative preservation of beta cell function.7<\/sup> Additional features (birth weight, extra pancreatic manifestations) provide guidance on the specific gene defect. However, family history is not a prerequisite since mutations can be novel ones.13<\/sup><\/p>\n

In the first patient, family history was consistent with monogenic DM and mild hyperglycaemia pointed to a GCK<\/em> deficiency. However, frank macrosomia in the two affected brothers suggested a mutation in HNF4A.<\/em>9<\/sup> Knowledge of the genetic diagnosis prompted a recheck of birth weights, which were in fact lower than initially reported but nevertheless included a macrosomic newborn. Fetal macrosomia is rare (but possible) in subjects with GCK<\/em> deficiency. In affected infants born to affected mothers, the rate of macrosomia has been reported to be 8,9%14<\/sup> and according to published information on birth weight mean and standard deviation,15-17<\/sup> the upper limit of birth weight in this group would range between 4163 and 4802 g.<\/p>\n

In the second patient, extrapancreatic manifestations clearly indicated a HNF1B<\/em> defect even though when a family history of diabetes with an autosomal dominant inheritance pattern was lacking. Once the genetic diagnosis was known, the revised family history was also suggestive of a HNF1B<\/em> mutation.<\/p>\n

Recently, a clinical prediction model has been developed to predict an individual\u2019s probability of having MODY among young adults with diabetes.18<\/sup> The calculator is available at http:\/\/www.diabetesgenes.org\/content\/mody-probability-calculator with an indication that it requires further validation. With the information available at the first consultation, it would give a MODY positive predictive value of >75% in the first patient and <5% in the second. This would not, however, have been a significant help in our patients since there was no problem in considering a MODY diagnosis in the first patient but only in assigning the required importance to the mild hyperglycaemia vs increased birth weight when seeking to identify a specific type. In the second patient, the problem was the incomplete family information that also contributed to the low positive predictive value of the calculator.<\/p>\n

Family history is included within monogenic diabetes criteria,7<\/sup> but these case reports illustrate that it can have its limitations even when information comes from apparently reliable sources. Clinical and biological features are also crucial for diagnosis.<\/p>\n

REFERENCES<\/span><\/p>\n

1. Yki-J\u00e4rvinen H, 1994. Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet 343: 91-95.
2. Barnett AH, Eff C, Leslie RD, Pyke DA, 1981 Diabetes in identical twins: a study of 200 pairs. Diabetologia 20: 87-93.
3. Redondo MJ, Yu L, Hawa M, et al, 2001 Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44: 354-362.
4. Kaprio J, Tuomilehto J, Koskenvuo M, et al, 1992 Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 35:
1060-1067.
5. Frayling TM, Evans JC, Bulman MP, et al, 2001 Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50: Suppl 1: 94-100.
6. Ledermann HM, 1995 Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet 345: 648.
7. Ellard S, Bellanne-Chantelot C, Hattersley AT, 2008 Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 51: 546-553.
8. Colom C, Corcoy R, 2010 Maturity onset diabetes of the young and pregnancy. Best Pract Res Clin Endocrinol Metab 24: 605-615.
9. Pearson ER, Boj SF, Steele AM, et al, 2007 Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4: e 118.
10. Bellann\u00e9-Chantelot C, Chauveau D, Gautier JF, et al, 2004 Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med 140: 510-517.
11. Zaffanello M, Brugnara M, Franchini M, et al, 2008 VTCF2 gene mutation leads to nephro-urological defects of unequal severity: an open question. Med Sci Monit 14: RA78-86.
12. Yorifuji T, Kurokawa K, Mamada M, et al, 2004 Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab 89: 2905-2908.
13. Heidet L, Decramer S, Pawtowski A, et al, 2010 Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol 5: 1079-1090.
14. De Las Heras J, Mart\u00ednez R, Rica I, et al, 2010 Heterozygous glucokinase mutations and birth weight in Spanish children. Diabet Med 27: 608-610.
15. Barrio R, Bellann\u00e9-Chantelot C, Moreno JC, et al, 2002 Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab 87: 2532-2539.
16. Estalella I, Rica I, Perez de Nanclares G, et al, 2007 Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf) 67: 538-546.
17. Shields BM, Spyer G, Slingerland AS, et al, 2008 Mutations in the glucokinase gene of the fetus result in reduced placental weight. Diabetes Care 31: 753-757 .
18. Shields BM, McDonald TJ, Ellard S,et al, 2012 The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 55: 1265-1272. <\/p>\n

Address for correspondence:<\/span>
Cristina Colom, Servei d\u2019Endocrinologia i Nutrici\u03cc, Hospital dos de Maig,
C\/ Dos de Maig 301. Barcelona 08025, Tel.: +34 93 507 27 00,
Fax: + 34 93 507 27 28, e-mail:cristinacomi@hotmail.com<\/p>\n

Received 23-08-2012, Accepted 07-03-2012 <\/p><\/div>\n

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Cristina Colom,1 Josep Oriola,2 Silvia Mart\u00ednez,3 Francisco Blanco-Vaca,4 Roser Casamitjana,2 Rosa Corcoy1,5 1Servei d\u2019 Endocrinologia i Nutrici\u03cc, Hospital de la Santa Creu i Sant Pau, 2Servei de Bioqu\u03afmica i Gen\u00e8tica Molecular (CDB), Institut d\u2019 Investigacions Biom\u00e8diques August Pi i Sunyer, Hospital Cl\u03afnic i Universitari, 3Servei de Bioqu\u03afmica Cl\u03afnica, Hospital de la Santa Creu i Sant Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[65,2,14],"tags":[1571],"class_list":["post-9437","post","type-post","status-publish","format-standard","hentry","category-volume-12-issue-3","category-journal-articles","category-volume-12","tag-family-history-glucokinase-hepatic-nuclear-factor-1-monogenic-diabetes"],"_links":{"self":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/9437","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/comments?post=9437"}],"version-history":[{"count":0,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/9437\/revisions"}],"wp:attachment":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/media?parent=9437"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/categories?post=9437"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/tags?post=9437"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}