J Pediatr Endocr Met 2014; 27(9-10): 961–965

Patient report
Juan Diego Mejia, Luisa Cervantes, Herminia Puerta, Mislen Bauer and Alejandro Diaz*

Neonatal diagnosis of a patient with
hypoparathyroidism, sensorineural deafness
and renal dysplasia (HDR) syndrome associated
with cerebral infarction
Abstract: Hypoparathyroidism, sensorineural deafness
and renal dysplasia syndrome (HDRS) is comprised of a
triad of conditions. It is an autosomal dominant condi­
tion caused by mutations in the GATA3 gene, located at
10p15, a critical region in the development of the embry­
onic parathyroid glands, inner ear, and kidneys. Here we
describe the case of a patient with all three components of
HDR syndrome diagnosed in the neonatal period who pre­
sented with cerebral infarction, hypocalcemia, and renal
anomalies. Upon chromosomal microarray he was found
to have an interstitial deletion at 10p, which produced a
partial deletion in the GATA3 gene.
Keywords: GATA3 gene; HDR syndrome; hypopara­
thyroidism; sensorineural deafness; renal dysplasia.
DOI 10.1515/jpem-2014-0004
Received January 19, 2014; accepted April 1, 2014; previously
published online May 23, 2014

Introduction
The triad of hypoparathyroidism, deafness, and renal
dysplasia is known as hypoparathyroidism, sensorineu­
ral deafness and renal dysplasia syndrome (HDRS) and
is also sometimes referred to as the Bakarat syndrome. In
1977, Barakat et al. reported the case of two brothers, ages
5 and 8 years, who had steroid-resistant nephrosis with
progressive renal failure, sensorineural deafness, and
*Corresponding author: Alejandro Diaz, MD, Division of Pediatric
Endocrinology, Miami Children’s Hospital, 3100 SW 62nd Ave,
Miami, FL, USA, E-mail: alejandro.diaz@mch.com
Juan Diego Mejia: Division of Pediatric Endocrinology, Miami
Children’s Hospital, Miami, FL, USA
Luisa Cervantes: Department of Radiology, Miami Children’s
Hospital, Miami, FL, USA
Herminia Puerta and Mislen Bauer: Division of Genetics, Miami
Children’s Hospital, Miami, FL, USA

hypoparathyroidism (1). In 1992, Bilous et al. reported on
two brothers and on two daughters of one of these brothers
affected by the condition (2). Based on these reports, an
autosomal dominant mode of inheritance was proposed
and confirmed by later research. In 1997, Hasegawa used
the acronym, HDR, in the report of a girl with this triad (3).
Deletions on specific regions within the short arm
of chromosome 10 have been found to produce complex
phenotypes, including those described in HDRS. Van Esch
et al. performed deletion-mapping studies in two patients
with HDRS and defined a critical 200 kb region inside 10p
that contains the GATA3 gene. Search for GATA3 muta­
tions in three additional probands with HDRS identified
one nonsense mutation and two intragenic deletions that
predicted a loss of function of the gene, as confirmed by
absence of DNA binding by the mutant GATA3 protein.
These results demonstrated that GATA3 is essential in the
embryonic development of the parathyroid glands, audi­
tory system, and kidneys, and showed that GATA3 haplo­
insufficiency produces the HDRS phenotype (4). In 1991,
Joulin et al. mapped GATA3 at 10p15 and, to date, several
mutations of this gene have been reported, including dele­
tion of the entire gene, intragenic deletions or insertions,
nonsense or missense mutations, and splice-site muta­
tions (5).
The clinical characteristics of HDRS are heterogene­
ous among patients and are dependent on penetrance.
Ferraris et al. described the phenotypical findings of 77
patients with HDRS reported in the medical literature
and found that 62.3% had the complete triad, 28.6% have
hypoparathyroidism and deafness, and 2.6% have deaf­
ness and renal disease (6). Familial studies of probands
with HDRS have identified GATA3 mutations in subjects
with deafness as the only clinical finding (7).
We describe the case of a boy who was diagnosed in the
neonatal period with the triad phenotype of the syndrome
who presented with a cerebral infarction. To our knowledge,
only two cases with this association have been reported.

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Mejia et al.: Neonatal diagnosis of a patient with HDR associated with cerebral infarction

Case report
The patient initially was referred to us at age 6 weeks for
evaluation of hypoparathyroidism. Review of his past
medical history showed he was the first living child of a
37-year-old mother and a 36-year-old father. They had a
previous miscarriage at 9 weeks of pregnancy. There was
no history of consanguinity between the parents. The
mother had hypothyroidism and received levothyroxine
during the pregnancy. On obstetric ultrasound, the patient
was found to have a right renal cyst and a hypoplastic left
kidney. A karyotype performed via amniocentesis showed
a normal pattern 46, XY. The patient was born at 39 weeks

A

B

C

D

of gestational age after an uncomplicated C-section. His
birth weight was 3140 g (25–50th percentile), birth length
was 51 cm (50–75th percentile), and head circumference
was 33.5 cm (10–25th percentile). His Apgar scores were 8
and 8 at 1 and 5 min, respectively. At birth he was noticed
to have bilateral preauricular tags and right hemiparesis
without dysmorphism. Soon after birth he was noted to
have apneic spells. CT and MRI of the brain showed a large
brain infarct in the territory of the left medial cerebral
artery (Figure 1). EEG showed attenuation of the activity
on the left hemisphere and electrographic seizures with
minimal clinical correlation, and he was started on phe­
nobarbital. Renal ultrasound showed absence of the right

Figure 1 (A) CT axial image demonstrates hypodensity in the left frontal and temporal lobes in the vascular distribution of the left middle
cerebral artery. (B) T2-weighted axial image demonstrates abnormal signal intensity in the same distribution with loss of the normal low
signal intensity of the cortex (“ribbon sign”). (C,D) DWI and ADC maps show restricted diffusion related to vasogenic edema involving also
the posterior corpus callosum indicating acute brain infarct.

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Mejia et al.: Neonatal diagnosis of a patient with HDR associated with cerebral infarction

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963

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Figure 2 (A) Sagittal image of the left kidney shows abnormal increased echogenicity of the left upper renal pole (arrow heads) with a small
cyst (arrow), consistent with renal dysplasia. (B) High resolution image obtained with a linear transducer allows better visualization of the
small cyst. The right renal fossa was empty (not shown).

kidney and a small left kidney with dysplasia of the upper
pole (Figure 2). Voiding cystourethrogram was normal.
During the neonatal period he had mild hypocalcemia
(lowest serum calcium of 7.6 mg/dL) (Table 1). He was also
found to have right cryptorchidism, a patent foramen ovale
that resolved without intervention, and absence of the 12th
right rib. The patient was discharged home at 10 days of
life with prophylactic anticonvulsive therapy, calcium car­
bonate, and vitamin D supplementation. Hearing screen­
ing the day of discharge was abnormal in the right ear. CT
of the temporal bones showed incomplete partition of the
cochleae (Figure 3) and abnormal morphology of the right
semicircular canal (Figure 4). Chromosome microarray

Table 1 Lab results from 2/8/11 to 2/10/11 during hospitalization
after birth of the patient.
Patient’s lab results during neonatal period
Date
BUN
Creatinine
Sodium
Potassium
Chloride
Glucose
Calcium
Prot total
Albumin

2/8/11

2/9/11

2/10/11

Normal range

14
1.39
135
5.4
100
71
7.6

11
1.09
142
6.3
106
66
8.2

7
0.83
140
5.6
104
63
8.8
5.9
2.7

6–21 mg/dL
0.3–1.00 mg/dL
136–145 mmol/L
4.0–5.7 mmol/L
98–108 mmol/L
70–110 mg/dL
9–11 mg/dL
6.4–8.2 g/dL
3.4–5.0 g/dL

The results for renal function test and calcium are in bold.

showed a 5 kb interstitial deletion at 10p14 producing a
partial deletion of the GATA3 gene. His parents’ chromo­
somal microarrays were normal, signifying his mutation
was de novo in origin.
At the time of the first evaluation he had normal
anthropometric measurements and was noted to have
delayed development and right hemiparesis. His labora­
tory results showed an intact PTH of 13 pg/mL (normal
range: 15–65 pg/mL) and a serum calcium of 9.2 mg/dL
(normal range: 8.6–10.2 mg/dL). His mother was advised
to ask her pediatrician to evaluate his calcium levels
in case of physiological stress (fever or illness) and/or
surgery. His calcium levels were normal upon following
evaluations; however, at 6 months, immediately after
orchiopexy, he developed severe hypocalcemia requiring
hospitalization for treatment with intravenous calcium
and calcitriol. During hospitalization, his creatinine and
BUN levels were normal, and a kidney ultrasound showed
normal growth of his left kidney with no progression of
the pelvocaliectasis. The patient was sent home on PM
60/40 formula, calcium carbonate, calcitriol, and vitamin
D3 supplementation.
On follow-up visits, calcitriol was discontinued, and
he was switched to regular formula due to normalization
of calcium and phosphorus levels. His calcium level had
ranged from 7.5 to 9 mg/dL, the recommended range for
patients with hypoparathyroidism to avoid hypercalciu­
ria. After his first birthday he was diagnosed with infantile
spasms. Subsequently, he has had significant regression
in his global development.

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Mejia et al.: Neonatal diagnosis of a patient with HDR associated with cerebral infarction

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Figure 3 CT of the temporal bones.
(A) Axial images of the right and left temporal bones of the patient demonstrate incomplete partition of the cochlea with fusion of the
middle and apical turns (long arrows). (B) CT images of the temporal bones in a normal patient show normal partition of the apical and
middle turns of the cochleae for comparison (short arrows).

A

B

Figure 4 CT of the temporal bone.
(A) Axial image shows deformity with focal narrowing of the lateral semicircular canal (long arrow). (B) Axial image in a normal patient
­provided for comparison (short arrow).

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Mejia et al.: Neonatal diagnosis of a patient with HDR associated with cerebral infarction

Discussion
HDRS is an autosomal dominant disorder that has been
described in more than 80 patients in the medical litera­
ture since the first report by Barakat et al. in 1977 (1). Most
patients have been diagnosed after the first month, and
following evaluation for hypocalcemic seizures and/or
hearing problems (8–10).
The presence of any of the components of this triad
should signal a physician to assess for the other two com­
ponents. Easy access to advanced laboratory tools, such
as the chromosome microarray, has allowed physicians
to make more timely and precise diagnoses of multiple
genetic conditions that previously required more cumber­
some and expensive individual genetic tests.
GATA3 is one of six members of the GATA family of
transcription factors. GATA3 encodes a 444 amino acid
protein that contains two transactivating domains (TA1
and TA2) and two zinc finger domains (ZnF1 and ZnF2).
ZnF2 is highly conserved and essential for binding of its
consensus response element, whereas ZnF1 stabilizes this
binding and interacts physically with the multiple-type
zinc finger friends of GATA (FOG) proteins (11). Any muta­
tion in the GATA3 that affects the transactivating domains
or the zinc finger domains will affect the functionality
of the protein, affecting the development of the organs
involved in the syndrome.
Our patient presented with right hemiplegia since
birth. A CT and an MRI of the brain performed a few days
after birth showed abnormality in the territory of the left
middle cerebral artery. Fujimoto et al. reported the case of
a Japanese boy with HDRS and recurrent cerebral infarc­
tions bilaterally at the level of the basal ganglia. This boy
presented with episodes of left hemiplegia beginning at
7 months of age, and months later, he presented with
right hemiplegia. CTs of his brain obtained at the time
of initial evaluation revealed areas of low-density in the
corresponding contralateral basal ganglia. Cerebral angi­
ography showed no abnormalities. This patient lacked
risk factors for cerebral infarctions, and Fujimoto et al.
described a possible relation between HDRS and cerebral
infarction as a new feature associated with the syndrome
(12). Shaw et al. reported on four patients with HDRS, one
of whom was found to have a small area of low-density
parenchyma in the left hemisphere upon evaluation for
seizures, suggesting cerebral infarctions (13).
This report demonstrates the importance of chromo­
somal microarrays in facilitating the identification of rare
conditions. In this specific case, the identification of a
deletion in the area of GATA3 allowed us to evaluate the
systems affected by mutations in this gene and to make

965

an early diagnosis. Thus, we were able to develop an early
management plan and prevent complications. Although
no causal relationship between HDRS and CNS infarction
has been established, to our knowledge our patient is the
third case in which this association has been described.
Further research is necessary to determine the nature of
this relationship.
Acknowledgments: We thank Elizabeth G. Lipman Diaz
for the help she provided reviewing and editing the origi­
nal manuscript.

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