Monogenic diabetes mellitus (DM) is extremely rare form
of the disease (less than 1-2% of all diabetes in young people),
with neonatal diabetes as a subset, and is usually suspected if
it’s diagnosed at less than 6 months of child’s age. About one
in half a million children all over the world are diagnosed
with neonatal diabetes at birth or a few weeks after. Clinically
two subgroups of neonatal DM are recognised: transient and
permanent. Transient neonatal DM resolves at a median of 12
weeks but as many as 50% of cases will ultimately relapse.
Permanent neonatal DM requires ongoing insulin treatment
when diagnosed. The majority of patients with transient
neonatal DM have an abnormality of imprinting of the ZAC
and HYMAI genes on chromosome 6q. Permanent neonatal
DM requires ongoing insulin treatment when diagnosed. The
commonest known cause of permanent DM are mutations in
the KCNJ11 gene encoding the Kir6.2 subunit of the β-cell K
ATP channel but not alone (fig).
We present the first case reported in Ukraine of a child
diagnosed with permanent neonatal DM resulting from a
eukaryotic translation initiation factor alpha kinase 3
(EIF2KA3) gene missense mutation of exon 15 (Wolcott-
Rallison Syndrome). It’s an autosomal recessive mutation
which usually shows its first signs at the age of 3 months.
A 1 years 10 mo old boy was referred to endocrinologist of
Ternopil Regional Children’s Hospital for further management as
he had been on insulin therapy for last 1 year and 8 months.
From anamnesis: he’s full-term child from second
physiological pregnancy and delivery, birth weight 2500 g.
Neonatal period was usual. Family history is unremarkable. In
age 6 weeks he was hospitalized due to moderate dehydration
and intoxication syndromes without vomiting or diarrhea.
Capillary blood glucose was 22 mmol/l (N=3,3-5,5) [396 mg/dl],
Hb1Ac = 9.662 % (N = 4,8-5,9), C-peptide = 0,27 ng/ml, (N = 0,9-
7,10) and manifestation of neonatal DM had been diagnosed.
General condition of the child quickly improved due to
combined insulin therapy.
By genetic DNA analysis of parents and child blood novel
EIF2AK3 gene missense mutation of exon 15 was revealed by
Sanger sequencing, that confirm the clinical diagnosis of
Wolcott Rallison syndrome. Analysis of all other known
neonatal diabetes genes did not identify a pathogenic
Confirmation of the gene mutation EIF2AK3 presence in
our patient was done by the laboratory of Exeter University,
Child grew and developed properly on regular basis-bolus
insulin therapy in daily dose of 0,36 U/kg body weight. The
course of diabetes was stable, glycosylated hemoglobin per
year observation was 8,2-8,5%.
In the age of 1 year boy was hospitalized to intensive care
unit due to grave general condition: fever, intoxication,
mild hypochromic anemia, hypoproteinemia, normal urea
and creatinine level, high transaminases, hyperbilirubinemia,
hypokaliemia. Hepatitis markers were negative. Glucose and
ketone bodies were absent in urine analyses. HbA1c was 8,6%.
Hepatomegaly, portions of free liquid in abdominal and
pericardial cavity, hydrocephaly were revealed at ultrasound
examination. Based on these signs and symptoms acute liver
failure was diagnosed.
After the intensive care for a month with insulin therapy,
parenteral nutrition, repeated blood transfusions, albumin
infusion, detoxification therapy, forced diuresis, correction of
electrolyte balance, the child's condition improved.
Mother had complained of lameness of left leg in child
which becomes more intensive and persistent during the last
months. By x-ray examination hypoplasia of the left hip join
was confirmed. Bone dysplasia is one of the typical sign of
Wolcott-Rallison Syndrome. Child was discharged from the
hospital in satisfactory condition.
In the age of two years child was hospitalized with acute
respiratory infection and sudden aggressive development of liver
failure which was fatal to the child despite of intensive care.
Wolcott-Rallison syndrome is an extremely rare condition
worldwide. It was named after Drs Wolcott and Rallison, who
first described this syndrome in three affected siblings. It
associates permanent neonatal or early-childhood insulin-
dependent diabetes and epiphyseal dysplasia. Other clinical
features that show variability among Wolcott-Rallison
Syndrome cases include mental retardation, hepatic and
pancreatic dysfunction, and neutropenia. Data on the
epidemiology of Wolcott-Rallison Syndrome are limited, and
the latest literature review on the subject suggested that less
than 60 of WRS cases were reported worldwide. However, the
condition has been recently found to be the commonest
genetic cause of permanent neonatal DM in consanguineous
families and in the Arab population.
Wolcott-Rallison Syndrome should be suspected in any infant
who presents with permanent neonatal diabetes associated
with episodes of acute liver failure. Molecular genetic testing
confirms the diagnosis. Early diagnostics is recommended in
order to ensure rapid intervention for episodes of hepatic
failure, which is the most life threatening complication.