Supplementary information: Clinical reports –CDH patients with chromosome deletions
Patients 1-4 have previously been described. 12, 15 The first child was born at 39 weeks
of gestation by C-section for fetal distress to a 27 year-old mother. She had a large, leftsided CDH with severe pulmonary hypoplasia, growth retardation with a birthweight of
1800 g (<10th centile), severe hypoplasia of the left heart and aortic arch, a cleft palate, a
two vessel umbilical cord and mild talipes equinovarus. Care was withdrawn shortly after
birth because of cardiac hypoplasia. Chromosome analysis from skeletal muscle showed
a normal female karyotype (46, XX) at 400-band resolution.
The second child was born to a 33 year-old mother at 32 weeks of gestation.
Birthweight was 2153g (>90th centile). Her malformations included a large, left-sided
CDH, pulmonary hypoplasia, cleft palate, transposition of the great vessels, aortic
stenosis, an atrial septal defect (ASD) and a ventriculoseptal defect (VSD), bilateral
hydroureter, ureteral atsresia, and a double uterus and septate vagina. External
examination also revealed aplasia cutis of the scalp, hypotelorism, a broad and flat nasal
bridge, low-set ears, micrognathia, neck webbing, a flexion contracture of the right hand
and narrow nails. The umbilical cord had two vessels. She was deceased shortly after
delivery. Chromosome testing on cord blood showed a normal female karyotype at 500600 band resolution (46, XX).
The third patient was born at 38 weeks to a 38-year-old mother. The child had
multiple malformations comprising CDH, hypoplasia of the left heart with a small VSD,
hydronephrosis, a small phallus with undescended testes, talipes and a two-vessel
umbilical cord. There was IUGR and the infant was dysmorphic with a prominent
forehead,
flat
nasal
bridge,
anteverted
nares,
low-set
and
dysplastic
ears,
retromicrognathia, angulated digits and hypoplastic nails, Amniocentesis showed 46, XY
but further studies on blood lymphocytes showed an unbalanced translocation involving
chromosomes 8 and 15 [karyotype 46,XY,der(15)t(8;15)(q24.1;q26.1)] at 750 band
resolution.
15
CGH array studies showed results consistent with normal copy number for
the genes in chromosome band 15q26.1, but deletion of the genes in chromosome band
15q26.3 and 15q telomere. 15
The fourth patient was the third child born to a 33-year old mother. A sonogram was
showed left-sided CDH and labor was induced at 22 weeks of gestation. A stillborn male
was delivered with a weight of 586 g (appropriate for gestational age). He had complete
absence of the left hemidiaphragm, severe pulmonary hypoplasia with incomplete
lobation of the right lung an ASD and VSD, malrotation of intestines and a micropenis
with cryptorchidism (normal for gestation). Other findings comprised a broad nasal
bridge, micrognathia and hypoplasia of the fingernails and toenails. Chromosome
analysis on amniocytes showed a normal male karyotype (46, XY) and fluorescence insitu hybridization (FISH) studies for chromosome 22q syndrome were negative.
The fifth patient was delivered at 37 weeks of gestation by elective C-section to a 32year-old mother. Birthweight was 2250 g (10th centile). A chest radiograph performed for
hypoxia showed left-sided CDH that was surgically repaired at 12 days of age. At six
months, weight was 4.6 kg, length was 59.5 cm and OFC was 40 cm (all parameters less
than fifth centile). He had frontal bossing, bilateral epicanthic folds, relative
hypertelorism (outer canthal distance measured 7.6 cm, 75-97th centile) a flat nasal
bridge, simple, low-set ears with bilateral preauricular pits, mild micrognathia, a bifid
uvula and a left, single transverse crease. Examination of the genitalia showed grade 4
hypospadias. He had central hypotonia but was able to roll from front to back, to push up
when prone and to focus on objects. A renal sonogram showed horseshoe-shaped kidneys
and an EEG was negative for seizures activity. G-banded chromosome analysis of
peripheral blood lymphocytes showed a deletion of 4p [46,XY,del(4)(p16)] at a 500 band
resolution and FISH for Wolf-Hirschhorn syndrome confirmed the deletion [ish.
del(4)(p16.3(WHSC1-)]. Both parents had normal chromosomes and normal FISH
results.
The sixth patient was born to a 27-year-old mother at 38 weeks of gestation.
Birthweight was appropriate for gestational age at 2350 g. Care was withdrawn shortly
after birth because of hypoxia and acidosis in association with multiple malformations.
Autopsy showed left CDH with severe pulmonary hypoplasia, a double outlet right
ventricle and a sub-aortic VSD, bilateral cleft lip and palate, a short neck with a cystic
hygroma,
coarse
facies
with
hypertelorism
and
micro-retrognathia,
bilateral
hydronephrosis and hydroureter, bilateral undescended testes and bilateral talipes
equinovarus. A karytoype performed on fetal skin showed 46,XY,del(1)(q32.3q42..2)
and the band resolution was not stated. A diagnosis of Fryns syndrome was made after
the prenatal sonogram and at autopsy.