Eleven new cases of del(9p) and features from 80 cases

J L HURET(1), C LEONARD(2), B FORESTIER(2), M 0 RETHORÉ(3), AND J LEJEUNE(3)

Journal of Medical Genetics 1988, 25, 741-749


Résumé :

SUMMARY We report 11 cases of del(9p) and review 69 previously published ones. Of the 80 cases, 39 have a del(9p) as the sole anomaly. The symptoms are typical and diagnosis should be suspected at birth. The sex ratio does not appear to be unbalanced. A cardiac murmur is often present but surgery is rarely necessary. Mean IQ is 48. The number of reported cases with an associated trisomy has previously been underestimated. Death in infancy, owing mainly to gross visceral malformations, occurs more often in cases of del(9p) with another unbalanced chromosome segment (16/41) than in cases of del(9p) as the sole anomaly (1/39).

Sommaire

Over 30 cases of del(9p) have been reviewed recently, the majority being de novo. We report 11 new cases of which seven have del(9p) as the sole anomaly and four have del(9p) with another unbalanced chromosome segment. In each of these two groups of patients, the order in which our cases are presented is a function of the length of the deleted segment, starting with the longest. It appears that dysmorphic features do not differ according to the length of the deletion. We summarize the features from 80 cases (table).

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Patients and methods

In the following descriptions, only features which are not included in the appendix will be described. A diagram showing the breakpoints on chromosome 9 is shown in fig 1. Each karyotype was performed with RHG banding except in case 2 where GTG banding was used.


Fig 1. - Breakpoints on chromosome 9p in present cases (left, cases 1 to 7: del (9p) as the sole anomaly; right, cases 8 to 11: del (9p) with another unbalanced segment).

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CASE 1*: 46,XX,del(9)(p21)

The proband (fig 2A) was the first child of healthy parents. Delivery was induced at 43 weeks' gestation.

* Cases cited in reference 56.

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CASE 2: 46,XY,del(9)(p22)

The parents of the proband had previously had 11 children, three of whom died in early infancy with-out any detectable malformation. There was apparent hypertelorism but a decreased interorbital distance was ascertained by radiography, small alae nasi, truncal hypotonia, and hypertonia of the extremities. Numerous seizures occurred but repeated electroencephalography did not show any anomaly. Surgery for craniostenosis was performed at the age of nine months. At the age of two years three months, dysmorphic features were unchanged (fig 2B). The patient understood simple requests but did not speak.

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CASE 3: 46,XX,del(9)(p22)

The proband (fig 2C) was the first child of healthy parents.

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CASE 4*: 46,XX,del(9)(p22)

A girl with seven healthy sibs was referred to us at the age of one year four months (fig 2D). She pre-sented with microcephaly, turricephaly, and tri-angular shaped auditory canals. Her bone age was advanced (two years at one year four months).

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CASE 5: 46,XX,del(9)(p23)

A girl with four healthy older sibs was referred to us when she was four years old. There were absent lacrimal ducts, deafness, kyphoscoliosis, and hypoplasia of the labia majora (fig 2E).

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CASE 6: 46,XX,del(9)(p23)

A girl (fig 2F) with one healthy sib was born after a pregnancy complicated by hydramnios. A cardiac murmur was present but no anomalies were de-tected with ultrasound. She rapidly developed res-piratory distress and was transferred to the intensive care unit. Radiography ascertained choanal atresia. Surgery was performed but the patient died at the age of two months from respiratory failure.

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CASE 7: 46,XX,del(9)(p23)

A four year old girl with two normal sibs was refer-red to us to confirm a probable trisomy 21. Clinical examination showed a moon shaped face, flat occi-put, epicanthus, low nasal bridge, but also trigonocephaly, long philtrum, widely spaced nipples, dolichomesophalangy, proximally placed thumbs, and five whorls (fig 2G).

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CASE 8*: 46,XY,-9,+der(9),t(9;12) (p21;q24)mat

The proband was born after an uneventful preg-nancy. There had been a previous miscarriage. At delivery, an infarction of the placenta was noted. The proband presented with trigonocephaly and tur-ricephaly, hypoplastic alae nasi, narrow ear canals, bilateral hexadactyly, hypospadias, and deafness (fig 2H). Numerous episodes of pneumonia occur-red. At the age of two months an advanced bone age was noted. He died from pneumonia at seven months. Necropsy showed a coarctation of the aorta. The karyotype showed monosomy 9p21?pter and trisomy 12q24?qter.

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CASE 9**: 45,XX,-9,-21,+der(9),t(9;21) (p21 or 22;q11 or 21)

The proband was the first child of healthy parents. Her Apgar scores were 8 at one minute and 4 at five minutes. Clinical examination (fig 21) showed a high, flat forehead, scaphocephaly, microphthalmos, very marked nasolabial furrow, slight prognathism of the upper maxillary bone, vermilion border of the upper lip visible only at the level of the cupid's bow, normal philtrum, crux cimbae and adherent lobuli, narrow auditory canals, small nails, lack of flexion crease on the third and fourth ringers, camptodactyly of the fifth finger, bilateral talipes valgus, no whorls, seven archs, umbilical and inguinal herniae, and a cardiac murmur. She died at the age of two years. Necropsy showed a ventricular septal defect and malformed kidneys. The karyotype showed monosomy 9p21 or 22?pter and monosomy 21pter?q11 or 21.

** Case partially reported in reference 55.

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CASE 10*: 46,XX,-9,+der(9),i:(5;9)(q32;p23)pat

The proband (fig 2J) was born at 32 weeks of pregnancy. Her parents had previously had five miscarriages. Growth retardation was noted one week before birth. There was a severe cardiac anomaly. The anus was anteriorly placed with a cleft towards the vagina. She died suddenly at the age of three months. Necropsy showed hypertrophy of the right ventricle, hypoplastic pulmonary arteries, a philtrum, nose with stunted tip, short, broad, and webbed neck with low hair line, excess of whorls on the fingers, dolichomesophalangy with extra finger flexion creases (countertype of trisomy 9p syn-drome), and the diagnosis should be suspected at birth. Other signs, although often present, are not specific for this condition (epicanthus, hypertelorism, microretrognathia, low set ears, abnormal tone, etc). A cardiac murmur is often present but cardiac surgery is rarely necessary. Herniae and minor abnormalities of the external genitalia and scoliosis or kyphosis are often encountered. After infancy, pyramidal tract signs, epilepsy, strabismus, nystagmus, and dental anomalies can occur (reported in three or four cases each). Mean IQ is 49 (SD 13) (range 33 to 73, n=14). Social adaptation is often good. One case has been diagnosed at the age of 61.

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9p deletion with another unbalanced chromosome segment

The number of del(9p) cases associated with a partial trisomy has been underestimated in the past since cases are often reported as 'a case of trisomy . . .'. We reviewed 41 cases of 9p- with an associated unbalanced chromosome segment, which is approximately half of the total number of cases. Most of them are inherited from a balanced translocation carrier (mother 25 cases, father 13 cases). The breakpoint can occur at 9p22 (nine out of 38 cases), the most common site in pure 9p-, but occurs mainly at 9p24 (23 out of 38 cases). This breakpoint has not been described in cases where 9p- is the sole anomaly, which may in part be because of the difficulty of karyotypic ascertainment of such a terminal deletion when isolated. Sex ratio appears to be 1.7 females/1 male ( etest, NS)*. Mean parental ages at birth are 25-2 (SD 3.7) (mother) and 27.9 (SD 4.3) (father). A family history of miscarriages or previous malformed children is present in half of the cases. The pregnancy is usually uneventful: mean birth weight is 2.9 kg (SD 0-6). Mean IQ is 46 (SD 9) (range 33 to 57, n=7). The associated unbalanced chromosome segment is variable (table) but four trisomy 13q, three trisomy 12q, three trisomy 10q, two trisomy 2q, two trisomy 5p, two trisomy 5q, two trisomy 7q, and two trisomy 16q were found in unrelated patients. Breakpoints on the trisomic segment are variable apart from 13q21 or 22 (four cases), 10q25 or 26 (three cases), 5q31 or 32, and 12q24 (two cases each). Trigonocephaly, long philtrum, dolichomesophal-angy, and hernia are often found in cases of del(9p)

* When cases of 9p- as the sole anomaly and cases with another unbalanced segment are pooled, a significantly unbalanced sex ratio appears. However, as the chromosomal mechanism is different, it does not seem valid to pool these two groups of patients. With another unbalanced segment. However, the phenomenon of epistasis is difficult to ascertain in certain cases since it cannot be based on objective investigations and measurements. It should be noted that 16 del(9p) patients with another unbalanced segment and only one patient with del(9p) as the sole anomaly have been reported to die in infancy.


Fig 2. - A, B, C Patients 1 to 3: cases of del(9p) as the sole anomaly. Arrow: dolichomesophalangy with extra finger flexion crease.


Table - Main features from 80 cases of del (9p)
As the sole anomaly (39 cases)With other unbalanced segment (41 coses)
No of cases or mean valueNo of informative casesNo of cases or mean valueNo of informative cases
Epidemiology
De novo34/342/40
Inherited (maternal)0/3425/40
Inherited (paternal)0/3413/40
Breakpoint
p240n=39*23n=38
p2334
p22259
p2152
p1340
p1210
Sex ratio15 M/24 Fn=3915 M/26 Fn=41
Maternal age (y)28.7(n=31)25.2(n=26)
Paternal age (y)31.5(n=30)27.9(n=20)
Family history1/3015/31
Abnormal pregnancy5/282/26
Birth
Normal term26/2925/27
Weight (kg)3.2(n=27)2.9(n=29)
Length (cm)49(n=11)48(n=17)
Head circumference (cm)34.416/1333.0? 7/18
Apgar9(n-7)5(n-6)
Mental development
Delay36/3630/30
Abnormal EEG2/94/8
Hypertonia7n=224n=19
Hypotonia1214
Cranium
Trigonoccphaly/prominent forehead32/3221/32
Flat occiput10/115/10 (prominent occiput 4/10)
Mid face hypoplasia6/74/6
Eyes
Upward slanting26n=3412n=23
Downward slanting57
Epicanthus22/277/14
Hypertelorism21n=2512n=22
Apparent hypertelorism31
Hypotelorism05
Small palpebral fissures14/146/8
Highly arched eyebrows9/128/15
Nose
Flat bridge27/2820/28(prominent bridge 6/28)
Anteverted nostrils30/3210/17
Mouth
Long philtrum32/3226/32
Small mouth8/119/20 (large mouth 5/12)
High arched and/or cleft palate25/2723/25
Micro/retrognathia26/3018/21
Ears
Low set27/3023/24
Abnormal lobuli17/219/10
Abnormal auricles9/115/6
Neck
Short/broad26/2725/26
Webbing15/188/11
Low hair line12/128/8
Trunk
Widely spaced nipples31/3114/14
Stiff joints, scoliosis9/218/22
Hernia9/3514/24
Cardiac murmur/cardiopathy16/3514/24
Abnormal external genitalia15/3610/24
Hand/foot
Abnormal calcancum9/2811/18
Dolichomesophalangy22/2316/19
Extra finger flexion crease10/150/3
Thumbs proximally placed6/70/4
Number of whorls6.3118/224.512/17
Increased total ridge count8/102/3
Distal axial triradius9/1413/16
Simian crease5/1811/17
Square, hyperconvex nails18/195/6
Hypoplastic ridges4/172/5
Early reports (refs 1 to 3) have not been included in this review since no banding was available, and it cannot be ascertained if del(9p) was the sole anomaly. Cases of del(9p) as the sole anomaly were reported in refs 4 to 28 and cases of del(9p) associated with another unbalanced segment in refs 5 and 29 ta 54. Present cases are included. *In one case, the deletion was interstitial: del(9)(pl3.3?p23). ? = increased. ? = decreased. Note: Other unbalanced segments were: dup(2)(q31?qter); dup(2)(q33?qter); dup(3)(q25?qter); dup(4)(p14?pter); dup(4)(q23?qter); dup(5)(p13?pter);dup(5)(p?); dup(5)(q31?qter); dup(5)(q32?qter); dup(6)(p21?pter); dup(7)(q2l?qter); dup(7)(q31?qter); dup(10)(q25?qtert); dup(10)(qter);dup(12)(p11?pter); dup(12)(q21?qter); dup(12)(qter); dup(13)(q21?qter); dup(13)(q22?qter); dup(15)(qter); dup(16)(q13?qter); dup(16)(qter);dup(18)(q12?qter); dup(20)(p?); del(9)(q00?q21); del(15)(pter?qll); del(21)(qll or 21?qtcr); t(9;13)(p22;a34) apparently balanced.

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