A child with multiple congenital anomalies and karyotype 46,XY,del(14)(q31q32.3): further delineation of chromosome 14 interstitial deletion syndrome.

Abstract

We report on an infant with a multiple congenital anomaly syndrome and severe developmental delay in association with a previously undescribed de novo interstitial deletion of chromosome 14 [karyotype: 46,XY,del(14) (q31q32.3)]. Comparison of the presented patient with previously reported cases of interstitial and terminal chromosome 14q deletions provides a group of patients monosomic for various overlapping portions of the distal half of chromosome 14q and suggests a limited similarity in phenotype among patients with common deleted 14q segments. All patients with distal 14q deletions were developmentally delayed, most were microcephalic and failed to thrive. Most of the patient's anomalies were limited to the face and head. Few major internal congenital anomalies were observed. These comparisons serve to further clarify possible associations of subchromosomal aberrations with specific phenotypes.

Full text

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American Journal of Medical Genetics 37:471-474 (1990)
Brief Clinical Report
A Child With Multiple Congenital Anomalies and
Karyotype 46,XY,del( 14)(q31q32.3): Further
Delineation of Chromosome 14 Interstitial Deletion
Syndrome
~~~ ~
~ ~~
Jerome L. Gorski, Wendy R. Uhlmann, and Thomas W. Glover
Division of Pediatric Genetics (J.L.G., W.R.U., T.W.G.), Departments of Pediatrics and Communicable Diseases
(J.L.G., T.W.G.), and Human Genetics (J.L.G.. T.W.G.), University of Michigan Medical Center, Ann Arbor,
Michigan
We report on an infant with a multiple congen-
ital anomaly syndrome and severe develop-
mental delay in association with a previously
undescribed de novo interstitial deletion of
chromosome 14 [karyotype: 46,XY ,de1(14)
(q31q32.3)I. Comparison of the presented pa-
tient with previously reported cases of inter-
stitial and terminal chromosome 14q dele-
tions provides a group of patients monosomic
for various overlapping portions of the distal
half of chromosome 14q and suggests a lim-
ited similarity in phenotype among patients
with common deleted 14q segments. All pa-
tients with distal 14q deletions were develop-
mentally delayed, most were microcephalic
and failed to thrive. Most of the patient’s
anomalies were limited to the face and head.
Few major internal congenital anomalies
were observed. These comparisons serve to
further clarify possible associations of sub-
chromosomal aberrations with specific phe-
notypes.
KEY WORDS: human chromosome 14, chro-
mosome deletion, chromo-
somal aberration, aneuploidy,
mental retardation, multiple
congenital anomalies
INTRODUCTION
Isolated de novo deletions of chromosome 14 are rare
and deletions resulting from the formation of ring chro-
mosome 14’s account for most reported cases [Schinzel,
Received for publication March 6, 1989; revision received April
11, 1990.
Address reprint requests to Jerome L. Gorski, M.D., Division of
Pediatric Genetics, Department of Pediatrics, D1109 MPB, Box
0718, University of Michigan, Ann Arbor, Michigan 48109.
0 1990 Wiley-Liss, Inc.
19841. We present a previously unrecognized de novo
interstitial deletion of chromosome 14 with a karyotype
46,XY ,del( 14Nq31q32.3) in an infant with developmen-
tal delay and multiple congenital anomalies. Compari-
son of the patient’s phenotype with 6 previously reported
patients with chromosome 14q deletions [Nielsen et al.,
1978; Hreidarsson and Stamberg 1983; Turleau et al.,
1984; Kawamura et al., 1985; Yamamoto et al., 19861
suggests that monosomy for subregion 14q31.lq32.1
may be associated with a limited number of facial char-
acteristics.
CLINICAL REPORT
A.S. was the 3841 g male infant of a 43 week preg-
nancy and was delivered by an uncomplicated repeat
cesarean section to a 26-year-old mother and a 27-year-
old father. His mother had one previous uncomplicated
pregnancy resulting in a normal infant. Pregnancy, de-
livery, and neonatal course were normal. No known
exposures to recognized teratogens were noted. There
was no family history of consanguinity, spontaneous
abortions, congenital anomalies, or mental retardation.
Developmental delay was apparent at 10 months at
which time the patient could not crawl, sit unsupported,
or pull to a stand. He crawled at 15 months and stood at
18 months. At 22 months he cruised, used a single word
and knew three body parts.
On physical examination at 22 months, all growth
parameters were below the 3rd centile with a head cir-
cumference (OFC) of 45.9 cm, length of 76.5 cm, and
weight of 9340 g. Physical manifestations included fine
sparse hair; bushy eyebrows with wide, medially flaring
margins; bilateral epicanthal folds; prominent, bilat-
erally cupped, apparently low-set ears with thick over-
folded helices and small dermal pits below the tragii
bilaterally; a broad, depressed nasal bridge; an up-
turned nose; full cheeks; a long well formed philtrum; a
bow-shaped, thin upper lip; a highly arched palate; a
bifid uvula; bilaterally dystrophic maxillary incisors; a
tongue with a depressed midline crease and septated tip;
micrognathia; diastasis recti; coronal hypospadias with

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472
Gorski et al.
Fig. 1. The patient at 15 months.
a cordae; right cryptorchidism; puffy, nonpitting edema-
tous distal extremities; a unilateral Simian crease; short
thin convex nails on all digits; and metatarsus adductus
bilaterally (Fig. 1). No focal neurological abnormalities
or pathological reflexes were noted during repeated ex-
aminations. Medical problems have been limited to ec-
zema, managed with topical steroids, and recurrent
bilateral otitis media necessitating bilateral tympa-
nostomies. Repeated ophthalmologic examinations have
been normal.
Laboratory investigations have included a normal T4,
TSH, creatinine, glucose, BUN, and urine amino and
organic acids. An echocardiogram was normal. Brain-
stem auditory evoked potentials were normal. Renal
ultrasonography showed mild right hydronephrosis. Pa-
tient and parents were unavailable for a,-antitrypsin
levels.
Cytogenetic Studies
The chromosomes of 20 cells were analyzed. The
modal chromosome number was 46. Prometaphase tryp-
sin-Giemsa and R banding chromosome analysis per-
formed on the patient’s cultured peripheral lymphocytes
and Epstein-Barr virus transformed lymphoblasts
showed an interstitial deletion of chromosome 14q
(Fig. 2); karyotype: 46,XY,de1(14)(q31q32.3) with no
other apparent chromosome rearrangements. His par-
ents’ chromosomes were normal.
DISCUSSION
This patient has a multiple congenital anomaly syn-
drome and severe developmental delay in association
with a heretofore unrecognized de novo interstitial dele-
tion of chromosome 14q31q32.3. We are aware of only 6
other reports of patients with isolated interstitial or
terminal 14q deletions [Nielson et al., 1978;
Hreidarsson and Stamberg, 1983; Turleau et al., 1984;
Kawamura et al., 1985; Yamamoto et al., 19861. The
cytological and clinical characteristics common to 2 or
more of our patient and those previously reported with
isolated 14q deletions are summarized for comparison in
Table I with the patient with the most proximal break-
point to the left. As illustrated in Figure 3, collectively,
these 7 patients are monosomic for various segments of
the distal half of chromosome 14q. At least 2 patients are
apparently monosomic for any given subregion of distal
14q. The segment of 14q monosomic in any patient
varies from approximately 6% for the 14q terminal dele-
tion [Hreidarsson and Stamberg, 19831 to 33% for the
patient with deletion 14q23q32 LTurleau et al., 19841.
Additionally, there is an apparent nonrandomness of
chromosome breakpoints among the deleted chromo-
somes. As summarized in Table I, two patients have
breakpoints at 14q23, 14q24.3, 14q31, 14q32.1, and
14q32.3. The significance of the apparent clustering of
14q breakpoints is uncertain.
la-- E
I1 2
11 2-
I 1 1 -
13-
9-
24 I-
n 3-
32 1-
f2 3-
2
Fig. 2. Partial karyotype of patient showing a schematic diagram of
the normal (left) and deleted (right) chromosome 14 bracketing the
patient’s Giemsa-trypsin banded normal chromosome 14 (left) and the
patient’s Giemsa-trypsin banded deleted chromosome 14q31q32.3
(right).

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TABLE I. Clinical Traits Common to Two or More Patients with Interstitial 14q Deletions
Turleau et al. Turleau et al. Kawamura et al. Yamamoto et al.
Our
[1978]
Hreidarsson et al.
[1984]
I19841
[1985]
[19861
_ _ _ _ . _
Patient
-
Mosaic
- -
[19831 - .
Nielsen et al.
Deleted segment
q23q24.2
q23q32
q24.3q32.1
q24.3q32.1
q31q32.3
q3lqter
q32.3qter
Gestational age
Term
37 wks
42 wks
37 wks
43 wks
Term
Term
Birth weight (g)
2860
+
2760
+
3800
+
2350
3841
+
4000
3250
+
Failure to thrive
-
-
Psychomotor
+
+
+
+
+
+
+
Microcephaly
+
+
+
+
+
Seizures
+
Feeding difficulty
-
-
Small palpebral
-
Epicanthal folds
+
Strabismus
+
+
Bushy eyebrows
+
+
+
-
+
-
+
-
Ear abnormalities
+
+
+
+
+
-
+
-
Small upturned nose
-
Carp mouth
-
+
Thin upper lip
Highly arched palate
-
Micrognathia
+
+
-
+
+
-
+
+
-
-
Excess of skin on nape
-
-
+
Heart defect
-
Renal anomalies
+ +
+
Cryptorchidism
f
+
Skeletal anomalies
+
+
-
+
+
-
+
-
Simian crease
-
retardation
-
- -
+
-
-
-
-
-
-
-
+
+
+
+
+
-
-
-
fissures
-
-
-
-
+
-
+
-
-
-
-
+
+
+
+
+
+
+
+
+
+
+
-
+
-
+
-
-
-
-
-
-
-
-
-
+
Abnormal dentition
+
-
-
+
-
+ +
-
-
-
-
-
-
-
+
+
+
-
+
-
-
-
-
-
+

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474
Gorski et a l .
3
1 3 - m - -
11.2-
11.1-
11.2-
13-
24.3-
32.3-
Fig. 3. Schematic diagram showing deleted segments of chromosome
14 in the present and previously reported cases: region a corresponding
to de1(14)(q23q24.2) “hrleau et al., 19841; b, deI(14Hq23q32) [Turieau
et al., 19841; c, de1(14)(q24.3q32.1) IKawamura et al., 1985; Yamamoto
et al., 19861; d, present case; e, del(l4Kq3lqter) [Nielson et al., 19781; f,
de1(14)(q32.3qter) [Hreidarsson et al., 19831.
Examination of patient phenotypes (Table I) shows
that all patients shared many relatively nonspecific
manifestations such as psychomotor retardation (7171,
failure to thrive (5171, micrognathia (6171, ear abnormal-
ities (6/7), and microcephaly (517). In comparison, major
internal structural congenital malformations were rela-
tively uncommon. No fatal or life threatening congeni-
tal malformations were reported. Observed major inter-
nal malformations were limited to congenital heart
defects in 2 patients without an apparent common
monosomic segment of chromosome 14. The defects con-
sisted of an atrial septa1 defect (ASD) and bicuspid aortic
valve [Turleau et al., 19841 and an ASD with partial
anomalous venous return [Hreidarsson and Stamberg,
19831. Cryptorchidism was reported in 3 patients. Renal
anomalies, consisting of isolated findings of renal hypo-
plasia, or horseshoe kidneys [Turleau et al., 19841 or
hydronephrosis (present patient) were observed in 3 pa-
tients. Various apparently patient specific skeletal ab-
normalities were reported in 6 of the 7 patients.
Most of the manifestations found in common among
the distal 14q deletion patients were craniofacial and
consisted of bushy eyebrows, a small upturned nose,
carp shaped mouth, highly arched palate, and abnormal
dentition (Table I) and were observed most commonly
among the 5 patients monosomic for 14q31q32.1. How-
ever, these characteristics were not uniformly observed
and some manifestations, such as bushy eyebrows, ab-
normal dentition, or a highly arched palate, were also
observed among the patients monosomic for other por-
tions of distal 14q such as 14q12q24.2 LTurleau et al.,
19841 and 14q32.2qter [Hreidarsson and Stamberg,
19831 respectively. Therefore, at this time, we conclude
that no definite 14q deletion syndrome is apparent.
Analysis of additional patients with distal deletions of
chromosome 14q may be helpful in identifying and char-
acterizing specific 14q deletion syndromes.
ACKNOWLEDGMENTS
We gratefully appreciate the assistance of Joanne
Owens in the preparation of this manuscript and Kotoku
Kurachi for his translation of the case report of Ka-
wamura et al. [1985]. This work was supported in part
by NIH Physician Scientist Award K11-HD00788 to
JLG.
REFERENCES
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with ring formation. J Med Genet 20:147-149.
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monosomy of 14q. J Pediatr Pract (Jpn) 48:32-34.
Nielsen J, Homma A, Rasmussen K, Ried E, Sorensen K, Saldana-
Garcia P (1978): Deletion 14q and pericentric inversion 14. J Med
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Schinzel A (1984): “Catalogue of Unbalanced Chromosome Aberra-
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