18p- syndrome: Presentation of two cases with alobar holoprosencenphaly

Abstract

Introduction: The syndrome by deletion of the short arm of chromosome 18 is an infrequent syndrome, and its phenotypical variability makes it difficult to recognize. Its most frequently observed clinical characteristics include mental retardation, growth retardation, craniofacial malformations, including long ears, microcephaly and short neck; other less frequent associated malformations include holoprosencephaly.
Case report: We present two patients with deletion of the short arm of chromosome 18, one presented a de novo mutation and the other was produced by a balanced translocation 6p/18p of maternal origin. Both patients presented alobar holoprosencephaly and cebocephaly, low-frequency clinical characteristics in this syndrome.
Discussion: alobar holoprosencephaly is a malformation appearing in 10% of patients with deletion of the short arm of chromosome 18; we review the probable physiopathology of holoprosencephaly in this syndrome.

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PACHAJOA, HARRY; SALDARRIAGA, WILMAR; ISAZA, CAROLINA
18p- syndrome: Presentation of two cases with alobar holoprosencenphaly
Colombia Médica, vol. 41, núm. 4, octubre-diciembre, 2010, pp. 367-372
Universidad del Valle
Cali, Colombia
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18p- syndrome: Presentation of two cases with alobar holoprosencenphaly
HARRY PACHAJOA, MD, PHD (A)1, WILMAR SALDARRIAGA, MD, MSC2,
CAROLINA ISAZA, MD, MSC3
SUMMARY
Introduction: The syndrome by deletion of the short arm of chromosome 18 is an infrequent syndrome, and its
phenotypical variability makes it difficult to recognize. Its most frequently observed clinical characteristics include mental
retardation, growth retardation, craniofacial malformations, including long ears, microcephaly and short neck; other less
frequent associated malformations include holoprosencephaly.
Case report: We present two patients with deletion of the short arm of chromosome 18, one presented a de novo mutation
and the other was produced by a balanced translocation 6p/18p of maternal origin. Both patients presented alobar
holoprosencephaly and cebocephaly, low-frequency clinical characteristics in this syndrome.
Discussion: alobar holoprosencephaly is a malformation appearing in 10% of patients with deletion of the short arm of
chromosome 18; we review the probable physiopathology of holoprosencephaly in this syndrome.
Colomb Med. 2010; 41: 367-72
Keywords: Syndrome by deletion of short arm of chromosome 18; (18p-) syndrome; Alobar holoprosencephaly.
Síndrome 18p-: Presentación de dos casos con holoprosencefalia alobar
RESUMEN
Introducción: El síndrome por deleción del brazo corto del cromosoma 18, es un síndrome poco frecuente y su
variabilidad fenotípica lo hace difícil de reconocer. Las características clínicas observadas con más frecuencia incluyen
retardo mental y de crecimiento, malformaciones c raneofaciales que incluyen orej as largas, microcefalia y cuell o corto; otras
malformaciones asociadas menos frecuentes incluyen la holoprosencefalia.
Reporte de casos: Se presentan dos pacientes con deleción del brazo corto del cromosoma 18, uno presentado de novo
y otro producido por translocación balanceada 6p/18p de origen materno. Ambos pacientes presentaron holoprosencefalia
alobar y cebocefalia, características clínicas de baja frecuencia en este síndrome.
Discusión: La holoprosencefalia alobar es una malformación que se presenta en 10% de los pacientes con deleción del
brazo corto del cromosoma 18; se revisa la probable fisiopatología de la holoprosencefalia en este síndrome.
Colomb Med. 2010; 41: 367-72
Palabras clave: Síndrome por deleción del brazo corto del cromosoma 18; Síndrome (18p-); Holoprosencefalia alobar.
1. PhD student in Biomedical Sciences, Assistant Professor, School of Basic Medical Sciences, Universidad del Valle.
Professor, Faculty of Health Sciences, Universidad Icesi, Cali, Colombia. e-mail: harrympl@yahoo.com
2. Assisting Professor, School of Basic Medical Sciences, School of Medicine, Universidad del Valle, Cali, Colombia.
e-mail: wsaldarriaga0608@yahoo.com
3. Full Professor, School of Basic Medical Sciences, Vice-rector of Research, Universidad del Valle, Cali, Colombia.
e-mail: carolinaisa@cable.net.co
Received for publication May 26, 2009 Accepted for publication August 18, 2009
© 2010 Universidad del Valle, Facultad de Salud Colomb Med. 2010; 41: 367-72
The syndrome by deletion of the short arm of
chromosome 18 (18p-) was first described by Grouchy
et al. in 1963; it is a syndrome with an estimated
prevalence of 1 in every 50,000 live births and its
phenotypic variability makes it difficult to recognize;
however, the most frequently observed clinical
characteristics include mental retardation, growth
retardation, low height, pectus excavatu m, craniofacial
malformations including long ears, ptosis, microcephaly,
and short neck1. There are case reports of holopro-
sencephaly diagnosed prenatally2.
Herein, we furnish a report of two patients with
deletion of the short arm of chromosome 18 (OMIM
146390) with alo bar holoprosencephaly, given that t his

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association i s infrequent and there are not many reports
of such in literature.
CASE REPORT 1
We present a female newborn, offspring of a 41-
year-old mother and product of a third pregnancy.
Prenatal ultrasound during the first, second, and third
trimesters revealed ventriculomegaly and alobar
holoprosencephaly. The birth took place at Hospital
Universitario del V alle in the city of Cali , with an Apgar
score of 8 and 9 on the first and fifth minute; placenta,
umbilical cord and blood vessels without alteration,
Ballard GA of 35 weeks, weight: 2535 g (p=3-25),
height: 46 cm (p=10), head circumference: 32 cm
(p=5), distance between inner edges: 16 mm (p<3),
distance between outer edges: 60 mm (p=3-25). The
physical exam found rounded face, sinophris, ocular
hypotelorism, cebocephaly, single nostril, and
micrognathia (Figure 1).
Paraclinical findings. Simple cerebral scan revealed
a single ventricle, fused thalamus; findings compatible
with alobar holoprosencephaly, echocardiogram: nor-
mal and renal ultraso und: normal. Cytogenetic findings
(g-banding karyotype, 750-band resolution): 46, XX,
of (18)(p11.2). The patient died one day after birth,
with the anatopathological exam revealing the findings
reported by the ultrasound and scan (Figure 2).
CASE REPORT 2
We present a female newborn, offspring of a
primigest 17-year-old mother. Prenatal ultrasound was
performed during the f irst, second, and third trimes ters;
the first two revealed no alterations and the third
showed evidence of asymmetry of the ventricular system.
The birth took place at Hospital Universitario del Valle
in the city of Cali, with an Apgar score of 8 and 9 on the
first and fifth minute; placenta, umbilical cord and
blood vessels without alteration, Ballard GA of 38
weeks, weight: 2200 g (p=5), height: 47 cm (p=10),
head circumference: 28 cm (p=5), distance between
inner edges: 15 mm (p<3), distance between outer
edges: 58 mm (p=3-25). The physical exam found fused
sutures, posterior and anterior fontanelle <1 cm, rounded
face, sinophris, ocular hypotelorism, cebocephaly, sin-
gle nostril, micrognathia, flat osseous palate, and pectus
excavatum (Figure 3).
Paraclinical findings. Simple cerebral scan revealed
a sole ventricle, fused thalamus, without evidence of
structures in the medial line; alobar holoprosencephaly
is concluded (Fi gure 4), echoca rdiogram: normal, renal
ultrasound: normal. Cytogenetic findings (g-banding
karyotype, 750-band resolution): 46, XX, of (18)(p11.2)
see Figure 5, in the Kar yotype the mother was found 46,
XX, t (6p, 1 8p) (18pter’™18p11.2: 6p24’™ 6qter), der.
18 (Figure 6).
Figure 1. Patient with deletion of short arm of chromosome 18, note cebocephaly and
ocular hypotelorism

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Figure 2. Cerebral anatomopathological analysis shows alobar holoprosencephaly
Figure 3. Patient with deletion of the short arm of chromosome 18. Note micrognathia, blepharoptosis,
sinophris, ocular hypotelorism, cebocephaly, short neck, and pectus excavatun.
The mother is evaluated without finding visible
malformations. The patient died 11 days after birth.
Ethics. In both cases, the parents signed an informed
consent allowing photographs to be taken and retrieval
of information from the clinical charts.
DISCUSSION
Nearly 150 cases have been reported with the
syndrome by deletion of the short arm of chromosome
18, and 85% of the cases have originated in a de novo

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Figure 5. Karyotype for patient 2
Figure 4. Simple cerebral CAT revealing holoprosencephaly
deletion and less frequently in
familial origin1. In case 2, the
newborn presents an 18p11.2
deletion, considered of mater-
nal origin, because of a finding
in the mother of a balanced
translocation 6p/18p, a finding
infrequently reported1. The
clinical characteristics found in
our cases are similar to those
described by other authors
(Table 1), although less frequent
findings were found like alobar
holoprosencephaly and the
presence of a single nostril3.
Approximately 50% of the
cases with holoprosencephaly
are associated to chromosome
alterations or to a monogenic
syndrome. This is the most
severe malformation in patients
with 18p- syndrome, which is
present in close to 10% of the
cases. The severity of the
holoprosencephaly varies from
cyclopy to facial malformations
with a central incisor. Four genes
for holoprosencephaly are
known: SHH (7q36), ZIC2
(13q32), SIX3 ( 2p21), and TGIF
mapped in the distal most part
of the short arm of chromosome
18 (18p11.3) 4. Such may be the
one affected in o ur patients with
a consequent abnormal ce rebral
formation and production of
alobar holoprosencephaly (Fi-
gure 7).
The clinical characteristics
or the gravity of the clinical
condition are not related to the
extension of the deletion of the
short arm of chromosome 18; as
can be noted by the description
of the two cases reported by
Hadedank5, the ratio between
women and men is 3 to 2, and

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gonodal dysgenesis has been reported along with
menstrual and fertility disorders1.
Among the clinical characteristics r eported, there is
also deficiency in the growth hormone, which may be
regulated by a critical region located in the 18p distal
region between 18p11.23 and 18pter. Analysis of this
region has revealed it contains a gene that codifies for
the pituitary adenylate cyclase-activating polypeptide
(PACAP), mapped in the 18p11.32 region. PACAP and
the growth release hormone (GRH) are part of the same
super-family of regulatory neuropeptides and both have
hypophysiotropic activity; low height is common in
patients with Monosomy 18p and it may be a result of
deficiency of the growth hormone secondary to an
alteration in a path involving the genes mentioned,
where PACAP would be absent because of the deletion4.
The prenatal diagnosis of this syndrome is possible
through amniocentesis; in addition, an increase of nuchal
translucency has been reported in this syndrome1.
Genetic advice for the parents should be done by a
specialized team, including a geneticist physician, to
Figure 6. Karyotype for the mother of patient 2
Figure 7. I deogram of the short arm of c hromosome
18, showing genes PACAP and TGIF (arrow), also
shown is the rupture point in both patients (double
arrow)

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estimate the risk of recurrence according to each case
and especiall y in cases presented throu gh translocations.
Care of these patients should be carried out by an
interdiscipl inary group according to age and findings in
each patient.
Conflict of interest. None of the authors has conflicts
of interest related to this study.
REFERENCIAS
1. Turleau C. Monosomy 18p. Orphanet J Rare Dis. 2008; 19:
4.
2 . Wang J-CC, Nemana L, Kou SY, Habibian R, Hajianpour MJ.
Molecular cytogenetic characterization of 18; 21 whole arm
translocation associated with monosomy 18p. Am J Med
Genet. 1997; 71: 463-6.
3. Zumel RM, Dranaude MT, Delicado A, Díaz de Bustamante
A, de Torres ML, Lopez-Pajares I. The 18p- syndrome. Ann
Genet. 1989; 32: 160-3.
4. Portnoi MF, Gruchy N, Marlin S, Finkel L, Denoyelle F,
Dubourg C, et al. Midline defects in deletion 18p syndrome:
clinical and molecular characterization of three patients. Clin
Dysmorphol. 2007; 16: 247-52.
5. Hadedank M, Trost-Brinkhues G. Monosomy 18p- and pure
18p- in a famil y with transloc ation (7, 18). J Med Genet. 1983;
20: 377-9.
* Data modified from reference 1
Table 1
Phenotype characteristics reported in the syndrome by deletion of the short arm of chromosome 18
and the findings in our patients*
Characteristics Partial monosomy Patient 1 Patient 2
18p (%)
General Low weight at birth 50 Present Absent
Low height 100 Present Absent
Mental retardation 80-100 Not assessable Not assessable
due to age due to age
Craniofacial Microcephaly 30 Present Present
Holoprosencephaly 10-20 Present Present
Blepharoptosis 35 Present Present
Midface hypoplasia Over 70 Present Present
Flat face Over 70 Present Present
Hypertelorism Over 40 Absent Absent
Epicanthic fold 30-40 Absent Absent
Mouth Long filtrum Unknown Present Present
Microstomy Unknown Present Present
Abnormal dentition 50 Unknown Unknown
Ears Low implantation Unknown Present Present
Long, dysplastic Over 70 Present Present
Genitourinary Renal hypoplasia Unknown Absent Absent
Hypogenitalism 50-60 Absent Absent
Others Cardiopathy Under 10 Absent Absent
IgA deficiency 10-20 Unknown Unknown
Cebocephaly Unknown Present Present