Homozygous Insulin Promotor Gene Mutation Causing Permanent Neonatal Diabetes Mellitus and Childhood Onset Autoantibody Negative Diabetes in the Same Family

Figures & data

Table 1 Salient Clinical Features Observed

Age of Diagnosis	26 d	2 yrs
Gestation age (weeks)	36	38
Birth weight (g)	1600	2800
Ketoacidosis at diagnosis	Yes	Yes
Diabetes autoantibodies	Negative	Negative
Age of remission	No remission	No remission
Current age (y)	12	10
Latest height	150.8 cm (−0.76 SDS)	127.7 cm (−1.55 SDS)
Latest weight	41.9 kg (−0.12 SDS)	25.05 kg (−1.54 SDS)
Current clinical status	PNDM	MODY
Current treatment	Insulin	Insulin
Current insulin dose	0.78 U/kg/d	0.51 U/kg/d
Latest HbA1c (%)	12.1	8.2
Site of mutation	INS promoter	INS promoter
c.DNA	c.-331C > G	c.-331C > G
Zygosity	Homozygous	Homozygous
Maternal mutation	Heterozygous	Heterozygous
Paternal mutation	Heterozygous	Heterozygous

Figure 1 Pictorial representation of the pedigree of the family.

Figure 2 Sanger sequencing and IGV analysis of the family.

Table 2 Describes All Previous Reports with the Homozygous INS Promoter Mutation and Their Phenotype

Promoter Mutations	Phenotype	Diabetes Autoantibodies
c.-331C>G 4 subjects from Saudi Arabia by Shaikh et al^Citation9	-NDM in all 4 subjects -PNDM in 2 subjects and TNDM in 2 subjects -Low birth weight in all subjects	-Islet cell antibody negative for one subject. -Test not done for 3 subjects.
c. −331C>G – 2 subjects c. −331C>A – 1 subject 3 subjects from Turkey by Demiral et al^Citation8	c. −331C>G Subject 1- PNDM, on multidose insulin injections at the current age of 6.1 years Subject 2- NDM remitted at 9 months, with no medication or dietary intervention, currently 3 years old c.-331 C>A PNDM remitted at the age of 2 months and relapsed at the age of 2.6 years with severe diabetic ketoacidosis (DKA)	-All 3 subjects are negative for autoantibodies
c.-331C>G 7 subjects from United Arab Emirates reported by Deeb at al^Citation10	NDM with variability in the age of onset, duration of disease and insulin requirement	Not done
c. −331C>A 2 subjects from Turkey reported by Demirbilek et al^Citation11	−1 subject had TNDM (remission at the age of 2 months) -Another subject had PNDM	Not done
c.-331C>G 1 subject from Turkey reported by Yildiz et al^Citation12	−1 subject with TNDM -Patient exhibited overt insulin resistance when glibenclamide was added to the treatment	Not done
c.-331C > A c.-331C > G c.-218A > C c. −332C>G c.-366_-343del, 24-base pair deletion c.-370-?_186+?del Reported by Garin et al^Citation5	-PNDM and TNDM -Low birth weight -Earlier age of diagnosis (median age at diagnosis – 1 week)	Not done

Abbreviations: PNDM, permanent neonatal diabetes mellitus; TNDM, transient neonatal diabetes mellitus; INS, insulin; MODY, maturity-onset diabetes of the young; GDM, gestational diabetes; GAD65, glutamic acid decarboxylase 65; IAA, insulin autoantibody; IA-2A, islet antigen-2 auto antibody; ZnT8A, zinc transporter 8; WES, whole exome sequencing; PCR, polymerase chain reaction.

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