American Journal of Medical Genetics 4R782-787 (1993)

Short Rib-Polydactyly Syndrome (SRPS) With Anencephaly and Other Central Nervous System Anomalies: A New Q p e of SRPS or a More Severe Expression of a Known SRPS Entity? Maria-Luisa Martinez-Frias, Eva Bermejo, Miguel Urioste, Javier Egues, and Jose A. Lopez Soler ECEMC Coordinating Group: ECEMC and Departamento de Farmacologia (M. -L.M. -F.) and ECEMC and Hospital Universitario San Carlos (M.U.), Facultad de Medicina (E.B.), Universidad Complutense de Madrid; and ECEMC Peripheric Group: Servicio de Pediatria, Hospital Virgen del Camino, Pamplona (J.E.); Servicio de Pediatria, Hospital Rafael Mendez, Lorca, Murcia (J.A.L.S.), Spain

We describe two patients with short rib-poly- dactyly syndrome (SRPS) from two unrelated Spanish families. These patients present clini- cal and radiological characteristics that over- lap those of the different established types of SRPS. In addition, one patient had anenceph- aly and the other patient had severe brain abnormalities with a family history of an older sister with anencephaly, and a brother diag- nosed with SRPS. This second family is inter- esting in that the two affected brothers pres- ent with different clinical and radiological findings; for example, one had ovoid tibiae and the other did not. This particular family shows that intrafamiliar variation is also ob- served within SRPS.

It remains unsettled whether these cases might be considered a new type of SRPS or a variant of an established entity or whether the differences between the SRPS represent variability or heterogeneity. Molecular studies may answer this question in the near future. 0 1993 Wiley-Liss, Inc.

KEY WORDS: short rib-polydactyly syn- drome, Saldino-Noonan, type I SRPS, Majewski, type I1 SRPS, Verma-Naumoff, type I11 SRPS, Beemer- Langer, type IV SRPS.

Received for publication April 5, 1993; revision received April 20, 1993.

Address correspondence to Dr. Maria-Luisa Martinez-Frias, ECEMC, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.

0 1993 Wiley-Liss, Inc.

INTRODUCTION Brain anomalies in the group of short rib-polydactyly

syndromes (SRPSs) are virtually restricted to Type I1 SRPS (Majewski) and consist of pachygyria, small vermis, and absence of olfactory bulbs [Majewski et al., 1971; Chen et al., 19801. In 1982, Nivelon-Chevalier et al. considered their patient with cebocephaly as an exam- ple of the Majewski type of SRPS. However, Gorlin et al. [19901 stated: “We cannot classify the infant with a Majewski-like syndrome and cebocephaly.” In 1991 Yang et al. published a patient with Beemer-Langer or Type IV SRPS with hydrocephaly and possible holoprosenceph- aly. More recently Tsai et al. [19921 published a SRPS child with encephalocele, concluding that the case could be an atypical form of Type I1 SRPS or another variant of Beemer-Langer or Type IV SRPS.

We report two new SRPS cases with severe brain anom- alies including anencephaly which, as far as we know, has not been described in any type of SRPS. These cases were identified through the Spanish Collaborative Study of Congenital Malformations (ECEMC) [see Martinez- F’rias et al., 1991 for ECEMC methodology].

CLINICAL REPORTS Patient 1 (304-51)

The propositus, a male, was stillborn at 36 weeks of gestation. The 34-year-old mother and 35-year-old father were not consanguineous, and the family history was unremarkable. The mother (G3P1) had two spontaneous abortions and surgery for an ovarian cyst 4 years before becoming pregnant with the propositus. She was being treated for menstrual irregularities with oral contracep- tives during the periconceptional period, and with pro- gestins from the 2nd to the 4th month of pregnancy. She had taken multivitamin supplements in the 3rd month. There were no other exposures, and the pregnancy was complicated only by polyhydramnios.

The child weighed 1,580 g (<3rd centile), had a length of 41 cm (3rd centile), and (Table I, Fig. 1) clinical find-

SRPS and CNS Anomalies 783

TABLE I. Non-Radiologic Diagnostic Criteria for the Four Forms of SRPS and Comparison With Our Cases

External appearance Cleft upper lip Reaxial polydactyly Postaxial polydactyly Syndactyly Omphalocele/umbilical

hernia Systemic abnormalities CNS

Holoprosencephaly Hydrocephaly NTD

Hypopl. epiglottis Urinary tract anom.

Renal agenesis Genital abnormalities Other Pol yh ydramnios Oligohydramnios Inheritance Consanguinity and/or

affected sib Normal karyotype Sex ratio (M:F) Sex

SRPS I Saldino Noonan

- - + + -

- - - -

+ + + + + + +

AR

4:9

SRPS I1 Majewski

+ + + + -

1 caseb +?d +?f + + + +

-

-

AR + + 1:l

SRPS I11 Verma

Naumoff

Pseudocleft

+ + -

-

+ + +

AR

+ 5:3

SR(P)S IV

Beemer Langer

+ 1 case'

+ + -

+?'

+?f + a, C. e

- + + +

-

- AR? + + 8:5

Present cases

Sib of 30(-5) 15(-23) 15(-23)

+ + + + + + + + + + ?

-

- - -

? ?

Anencephaly ? ? ? + + -

-

?

M -

+ + - - - - + ? ?

sib

?

M -

a Described by Hennekam [19911.

'Published by Yang et al. [19911. Reported by Nivelon-Chevalier et al. [19821.

Rewrted bv Sharma et al. 119921. De'scribed 6y Lin et al. [19911. Tsai et al. [19921.

ings of edema, anencephaly, bilaterally cleft upper lip, short limbs, pre- and post-axial polydactyly of the hands and feet, syndactyly, and sexual ambiguity.

Radiological studies (Table 11, Fig. 2) showed very short ribs and long tubular bones, bowed ulnae and hypoplastic radii, inadequately ossified, small vertebral bodies with coronal clefts, and small abnormally con- toured iliac bones with horizontal, trident-shaped ace- tabular margins. There were longitudinal metaphyseal spurs in both femora and humeri. The tibiae were very short, but longer than the fibulae and not ovoid shaped. Corticomedullary differentiation was good.

Chromosome studies and autopsy were not performed.

Patient 2 (154-231) The propositus, a stillborn male, was the 4th preg-

nancy of a 30-year-old mother and a 35-year-old father, both healthy and non-consanguineous. The infant was delivered, in 1985, by cesarean section at 36 weeks of gestation because of severe polyhydramnios and ultra- sonographic and radiologic diagnoses of anomalies. The birth weight was 2,920 g (2540th centile). The mother drank a glass of wine daily; there were no other expo- sures during pregnancy.

At birth (Table I, Fig. 3a-d) the fetus had deep-set eyes (Fig. 3a), micrognathia, redundant skin on the neck (Fig. 3b), short limbs, pre- and post-axial polydactyly of

the hands (Fig. 3c), and preaxial polysyndactyly of the feet (Fig. 3d), narrow chest, and hypogenitalism.

Radiologic studies showed (Table 11, Fig. 4) poor ossi- fication, coronal clefts in some vertebrae, short and hori- zontal ribs, minimal bowing of both femora, ovoid tibiae, abnormal iliac bone contour, and trident-shaped lower margins of the pelvis. There were some longitudinal metaphyseal spurs (Fig. 5a,b). Corticomedullary differ- entiation was good.

Autopsy confirmed pulmonary hypoplasia, agenesis of the cerebellum, single cerebral ventricle, agenesis of the olfactory bulbs and tracts, agenesis of the corpus callosum, hydrocephaly (Table I), and hypoplasia of the adrenal glands.

Chromosomal analysis was not performed, and the karyotypes of the parents were normal.

The first pregnancy of this couple ended in 1977 in a liveborn female who was described as having anen- cephaly, and about whom there is no further informa- tion. The second pregnancy was a male born in 1978 at 39 weeks of gestation, who was reported as having SRPS and dying 30 minutes after birth. Autopsy stated that the baby had (Tables I and 11) flat occiput, cleft lip and palate, low-set ears, postaxial polydactyly of the hands and preaxial polydactyly of the feet, narrow chest, short ribs, and mild shortness of the lower limbs. Radiologic report described short ribs, relatively short tibiae longer

784 Martinez-F'rias et al.

Fig. 1. Clinical appearance of patient 1. Fig. 2. Radiograph of patient 1.

than his fibulae and not ovoid in shape (Table 11). The autopsy also documented dehiscent cranial sutures, ab- sence of olfactory tracts, single cerebral ventricle, hy- drocephaly, pulmonary hypoplasia, open ductus a r k - riosus, and undescended testes (Table I). The third baby, born in 1981, was a normal male.

DISCUSSION Although the clinical and radiological findings of the

different types of lethal SRPS strongly overlap, most of the authors agree that the Majewski type (type 11) is clearly distinguishable from types I and I11 [Sillence, 1980; Jones, 1989; Gorlin et al., 19901; however, discrim-

TABLE 11. Radiolopic Diamostic Criteria for the Four Forms of SRPS and ComDarison With Our Cases

~~

Short cranial base Macrocephaly Flat occiput High clavicles Rounded scapulae Vertebral anomalies Pelvic abnormalities

abnormal contour flat acetabulum trident shaped

Tibiae longer than fibulae Ovoid tibiae Bowed femora Good corticomedullary differentiation Metaphyseal spurs

longitudinal

SRPS I Saldino SRPS I1 Noonan Majewski

SRPS 111

Verma Naumoff

SR(P)S IV

Beemer Langer

? + ? + + + +

-t

+ +

Min. -

Present cases

Sib of 30(-5) 15(-23) 15(-23)

? ? ? ? ?

? ? + ? ?

-

- n

+ + +

-

+ + + + + + + + +

-

-

Fig. 3. Patient 2. a: Clinical appearance; b: lateral view; c: polydactyly of hands; d preaxial polysyn- dactyly of feet.

786 Martinez-Mas et al.

Fig. 4. Radiograph of patient 2.

ination between the Majewski and Beemer-Langer types of SRPS is more difficult and sometimes impos- sible [Hennekam, 19911.

Our first patient (30-[-5]), had in common with Ma- jewski patients, a cleft upper lip, pre- and post-axial polydactyly, and good corticomedullary differentiation. However, his tibiae were longer than his fibulae and he presented vertebral and pelvic abnormalities similar to those described in Saldino-Noonan syndrome, Verma- Naumoff syndrome, and to some degree, in Beemer- Langer syndrome. Not only do the clinical and radiologic characteristics of this patient overlap the four accepted types of SRPS (Majewski and non-Majewski forms), but he also had anencephaly, which has not been observed previously in any type of SRPS. In a recent paper Tsai et al. [19921 described a child with SRPS and encepha- locele and concluded that their patient could represent an atypical form of SRPS I1 or another variant of the Beemer-Langer syndrome. Our patient (30-[-51), who had a neural tube defect, differs from the patient de- scribed by Tsai et al. [19921 and cannot be classified in any of the established types of SRPS.

We have the same difficulty in classifying the second child. The baby’s ovoid tibiae were much shorter than his fibulae, which together with the preaxial polydac- tyly are compatible with the Majewski type of SRPS. However, the infant also had pelvic and vertebral abnor- malities, as infants with the non-Majewski types. The

infant had micrognathia, agenesis of the olfactory bulbs and tracts, a single cerebral ventricle, agenesis of the corpus callosum, agenesis of the cerebellum, and hydro- cephaly. There are only four previous reports of hydro- cephaly in children with the diagnosis of lethal SRPS: one reported by Sharma et al. [1992] in a baby with Majewski type, and the other three in patients with Beemer-Langer syndrome. One was published by Yang et al. [1991]; another one who also had manifestations of orofaciodigital syndrome type I was reported by Lin et al. [19911; and the third was published by Hennekam [1991]. We consider that our patient did not have Bee- mer-Langer syndrome either. Some of his findings are compatible with the hydrolethalus syndrome, as in the two infants with SRPS who were described by Sharma et al. [19921 who also had micrognathia and gross brain abnormalities such as absence of the corpus callosum and severe hydrocephaly. These authors suggested that the two patients overlapped Majewski SRPS and the hydrolethalus syndrome, as our patient does.

The family history of this second patient is also very interesting: the first sib, a girl, was anencephalic, and the second, a male, had a SRPS. Although we have no more information on the anencephalic infant of this family, the observation of another unrelated patient who had SRPS and anencephaly allows us to speculate that the anencephalic child in this family might also have had a SRPS. The previously born brother diag- nosed with SRPS had cleft lip and palate, and pre- and post-axial polydactyly, all of which would be compatible with the Majewski type of SRPS. However, his tibiae were just a little bit shorter than his fibulae, and not ovoid as would be expected in this type 11. After a normal male, the propositus was born and, contrary to his af- fected brother, had ovoid tibiae which were much shorter than his fibulae. To the best of our knowledge, this is the first time an affected sib had ovoid tibiae and the other did not. Hennekam [1991] claimed the necessity of this observation to support the conclusion that Majewski syndrome and the Beemer-Langer syndrome were dif- ferent expressions of the same condition.

Our cases of SRPS associated with severe brain anom- alies and NTD, could represent a more severe expression of SRPS. In fact the mother of the first patient reported here has had three pregnancies, of which two were spon- taneous abortions and the third was the propositus. It may be possible that the miscarriages were severe forms of this spectrum. Although the parents were not consan- guineous in either case, all four grandparents came from small towns, particularly in the second case.

We have described two patients who, besides present- ing severe brain defects, including anencephaly, also share the clinical and radiological characteristics of all four types of SRPS, making it extremely difficult to classify them as any particular type. Although these two patients could be considered as having a new type of SRPS, given the extensive overlap that exists in all the published types of lethal SRPS, including most of the seven types proposed by Spranger and Maroteaux 119903 and ours, we suggest that all of them constitute vari- ability of a single entity [Cherstvoy et al., 1980; Rodriguez et al., 1980; Bernstein et al., 19851. Moreover, we have

SRPS and CNS Anomalies 787

Fig. 5. a,b Radiographs of patient 2. Note longitudinal metaphyseal spurs.

also observed the same clinical and radiological vari- ability (Table I and 11) within the same family (our second patient and his brother). This intrafamilial vari- ation supports the suggestion of a single entity which may include all types of lethal SRPS. This condition could be due, as has been stated previously [Sillence, 1980; Cherstvoy et al., 19801, to point mutations at the same locus, or at different gene loci, or to variable ex- pressions of a single mutant gene. However, the conclu- sion must be established by molecular studies.

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