American Journal of Medical Genetics 41:258-262 (1991)

Familial Holoprosencephaly, Heart Defects, and Polydactyly Raoul C.M. Hennekam, Gerard Van Noort, and Alfred A. De La Fuente Clinical Genetics Center, Utrecht (R.C.M.H.)and Streeklaboratorium voor Pathologie, Enschede (G.V.N.,A.A.D.L.F.), The Netherlands We describe a pair of sibs with microcephaly, hypoplastic nose, cleft lip/palate, a complicated Fallot-likecardiac defect, and holoprosencephaly and polydactyly. One sib appeared t o have normal chromosomes. The healthy parents were second cousins. This constellation of signs has been described before in at least 14 other patients, and was possibly present in several others. Although there is overlap with a number of similar conditions,especially hydrolethalus syndrome, this probably represents a separate entity. Three pairs of sibs and consanguinity in 3 families point to autosomal recessive pattern of inheritance.

KEY WORDS: postaxial polydactyly,cleft lip/ palate, cardiac defect, autosoma1 recessive inheritance, hydrolethalus syndrome, pseudotrisomy 13 syndrome INTRODUCTION Holoprosencephaly, cardiac defects, and polydactyly are usually associated with a chromosome abnormality, especially trisomy 13. Here we present 2 sibs born to consanguineous parents with this constellation of signs and with normal chromosomes, and compare them with earlier cases from the literature. CLINICAL REPORTS Patient 1 This girl was born the first child of healthy, consanguineous parents (second cousins), who were both 23 years old. At a postmenstrual age of 36 weeks the mother was admitted to the hospital because of fetal growth retardation. Ultrasound measurements corresponded to 33 weeks of gestation. The fetus died at 39 weeks of gestation. A severely malformed and macerReceived for publication October 16, 1990; revision received February 8, 1991. Address reprint requests to R.C.M. Hennekam, M.D., Ph.D., Clinical Genetics Center Utrecht, P.O. Box 18009,3501 CA Utrecht, The Netherlands.

0 1991 Wiley-Liss, Inc.

ated child was born, weighing 1,850 g, with length of 43 cm, crown-rump length 30 cm, and head circumference (OFC) of 28.5 cm (all below the 3rd centile for age). Postmortem examination showed microcephaly, hypotelorism, severely hypoplastic nose, median cleft palate, bilateral simian creases, and unilateral postaxial polydactyly (postminimus) of the left foot. The brain weighed 270 g (belowthe 3rd centile for age, 75th centile for weight). Olfactory bulbs and tracts were present. Except for dysplastic cerebellar foci no abnormalities were found. The heart showed a Fallot-like complex defect: extremely narrow infundibular outflow tract of the right ventricle, and large perimembranous ventricular septal defect with overriding aorta. In addition, a muscular ventricular septal defect, ostium secundum type atrial septal defect, persistent left superior vena cava, and right aortic arch with mirror-image branching pattern were present. The kidneys were very small (5.6g; N 20.5 & 4.8 g), but microscopically without cystic changes. Total body roentgenogram showed hypotelorism (intraorbital distance 0.8 cm), and hypoplasia of the frontal bones, but no other abnormalities (Fig. 1A).Fibroblasts failed to grow. Chromosomal analysis of lymphocytes of the parents gave normal results. At that time no diagnosis was made. Patient 2 The second child (second cousins) was born 2 years later. Amniocentesis at a postmenstrual age of 16 weeks showed normal chromosomes (46,XY). Unfortunately, no ultrasound examination was done at that time. The mother did not return to clinic before the 37th week, when ultrasound disclosed microcephaly and a complicated heart defect. A boy was born at a postmenstrual age of 41 weeks. Birth weight was 3,160 g (25th centile),body length 47.5 cm (3rd centile), crown-rump length 35.5 cm, and OFC 32 cm (below 3rd centile). Clinical examination (Fig. 2): bilateral severe microphthalmia, hypotelorism, flat rudimentary nose, bilateral cleft upper lip and palate, and small, apparently low-set, posteriorly angulated, abnormally small ears. There were short stubby hands, simian creases, a short neck, micropenis, and bilateral cryptorchidism. Total body roentgenograms confirmed the presence of hypotelorism (intraorbital distance 0.7 cm) (Fig. lb). No

Familial Holoprosencephaly

259

Fig. 1. Skull films of Pt.1 (A) and Pt.2 (B). Note hypotelorism and strong mutual resemblance.

pachygyria. No olfactory bulbs or tracts, no crista galli, and no perforations for olfactory nerve filaments were found. The optic nerves were hypoplastic. At the orbital surface of the frontal brain pole the interhemispheric fissure was very shallow and a midline continuity of the basal parts of the frontal lobes was present. On section (Fig. 3A) the corpus callosum was thin, and absent in its frontal part. There was no septum pellucidum, and a broad communication existed between the lateral ventricles. The third ventricle existed as a narrow aqueductlike structure originating in the bottom of the communicating lateral ventricles, with midline continuity at the level of corpus striatum and thalamus (Fig. 3B). In the heart a complex malformation was present: a large perimembranous ventricular septa1 defect, overriding aorta, and atresia of the right ventricular outflow tract and pulmonary valve. In addition, the Ebstein malformation was present with a small dysplastic and caudally displaced tricuspid valve, the inlet portion of the ventricle becoming part of an enlarged and hypertrophic right atrium. The right ventricle was hypoplastic and thick-walled. Autopsy further showed an abnormal lung lobulation, and horseshoe kidneys. Fig. 2. Pt. 2. Note bilateral cleft of upper lip, philtrum-premaxilla anlage, flat nose, deep-set eyes, and hypotelorism.

other abnormalities were found Computerized tomography of the brain showed agenesis of the olfactory nerves, hypoplasia of the optic nerves, and hypoplasia of the corpus callosum. The child died on day 8 because of cardiorespiratory failure. At autopsy the frontal bones were found to be united without apparent metopic or sagittal suture. The brain weighed 277 g (below the 3rd centile) and showed

DISCUSSION A comparison of the present sibs to all literature cases with possibly the same syndrome, and to hydrolethalus syndrome, Meckel syndrome, Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome (SLOS) type 11, and some related case reports is made in Table I. The first patient with the combination of holoprosencephaly, heart defects, and postaxial polydactyly was described by Young and Madders in 1987. Eleven other patients were described since then [AndrB et al., 1988; Atkin, 1988;Moerman and F'ryns, 1988;Shiota and Tan-

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Possibly related case reports'

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Autosomal recessive holoprosencephaly, heart defect, and polydactylye 2

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Abbreviations: - ,absent; + ,present; + + ,present in more than 50%of cases; + + + ,present in more than 75% of cases; occ, occasionally;P, proboscis; ASD, atrial septal defect; VSD, ventricular septal defect; AV, total atrioventricular channel; F, Fallot-like anomaly (see text); CI, ASD + VSD + absent septal cusp of tricuspid valve; C2, dextrocardia + tricuspid atresia + overriding truncus communis; Pe, preaxial; Po, postaxial; 0,omphalocele;H, Hirschsprung; HV, hemivertebrae; PDD, pancreatic ductal dysplasia; BA, bilateral anotia; SL, synechia between lips; DM, diastematomyely; SS, small spleen; HK, horseshoe kidney; C, renal cysts; D, renal dysplasia; A, renal agenesis; CA, choanal atresia; AT, absent tibiae; CLP, cystic livedpancreas; ST, small tongue; HH, hypothalamic hamatoblastoma; IA, imperforate anus; TAR, thick alveolar ridges; S, syndactyly toes 2 and 3; Ca, cataract; CF, contractures of fingers. "References: 1, Young and Madders [19871;2, Andre et al. 119881;3, Moerman and Fryns 119881;4, Shiotaand Tanimura [19881;5 and 6, Atkin 119881; 7, Hewitt et al. [1989];8, Ramaekers et al. [19911; 9 and 10,Bachman et al. t19901; 11, Antich et al. 119901; 12, Cohen and Gorlin 119911;13,Fitchand Pinsky 119731; 14, Rowlatt and F'ruzansky [1980]; 15 and 16, Present cases; 17, Krassikoff et al. 119871; 18, Donnai 119881; 19, Meinecke 119891; 20, Tollner et al. [19811; 21, Grote et al. 119841.

Microcephaly Hydrocephaly Holoprosencephaly Hypoplasia cerebellum Occipital encephalocele Micro/Anophthalmia Severe hypoplasia nose Cleft lipipalate Micrognathia Heart defects Abnormal larynx, traches, bronchi Lung abnormal lobulation Renal abnormalities Malrotation gut Genital abnormalities Polydactyly Hands Feet Clubfoot Other abnormalities

1

TABLE I. Comparison of t h e Presently Described Sibs to Similar Cases From Literature, a n d to Hydrolethalus Syndrome, Meckel Syndrome, Pallister-Hall Syndrome, and SLOS Tvpe I1

Familial Holoprosencephaly

Fig. 3. Pt. 2. Brain sections. A Frontal section of frontal lobes showing midline continuity and absence of the frontal part of corpus callosum.B Frontal section at the level of corpusstriatum showingthin corpus callosum, absent septum pellucidum and third ventricle, and midline continuity.

imura, 1988; Hewitt et al., 1989; Antich et al., 1990; Bachman et al., 1990; Ramaekers et al., 1991; Cohen and Gorlin, 19911. Two earlier descriptions [Fitch and Pinsky, 1973; Rowlatt and Pruzansky, 19801 probably represent the same entity [Cohen and Gorlin, 19911. In addition, the patients described by Krassikoff et al. [19871, Donnai [19881, and Meinecke [19891 may have had the same entity, as was suggested by Meinecke [1989]. However, the presence of an occipital encephalocele in these patients makes the diagnosis less certain. In the present pair of sibs, only one child had polydactyly and the other one only had holoprosencephaly.This was also found in the pair of sibs described by Atkin [1988]; the infant described by Rowlatt and Pruzansky [19801 did not show polydactyly either. This may indicate that postaxial polydactyly and holoprosencephaly are not obligate manifestations of the present condition. In patients lacking these manifestations, recognition is probably possible only through affected sibs. If such sibs are not available, the diagnosis remains tentative. The fetus described by Grote et al. [19841has a great

261

number of similarities with the presently described sibs. Especially the heart defect in their patient shows a remarkable resemblance. The presence of both pre-, meso-, and postaxial polydactyly, and the absence of the tibiae, make lumping with the other above-mentioned patients, in our opinion, not justified. The diagnosis in the patient described by Tollner et al. [19811 remains undetermined because of the presence of preaxial polydactyly and the absence of holoprosencephaly. It seems prudent to separate this case until additional similar cases are described. Bachman et al. [19901 have suggested that holoprosencephaly may be a component manifestation of the hydrolethalus syndrome. Both conditions have a number of characteristics in common (TableI). In most patients with hydrolethalus syndrome there is polyhydramnios, an occipital bony defect, a tongue abnormality, severe micrognathia, and the polydactyly of the feet is more often preaxial. In addition, the hydrocephaly is massive, holoprosencephaly is rare (if ever present in a frank form [Cohen and Gorlin, 199111, and abnormalities of the respiratory system are frequently found [Krassikoff et al., 19871. In our opinion these findings are sufficient to consider the hydrolethalus syndrome and the presently described syndrome of holoprosencephaly, cardiac defects, and polydactyly as separate entities. Others were of the same opinion [Donnai, 1988; Cohen and Gorlin, 19911. Cardiac defects and postaxial polydactyly are well known findings in the SLOS, so-called type I1 [Curry et al., 19873. The presence of cataract, thick alveolar ridges, renal agenesis, sex reversal, and syndactyly of toes 2 and 3, and the absence of holoprosencephaly will normally be sufficient to differentiate between the two syndromes, although especially in case 6, described by Atkin [19881, the differentiation is mainly possible through the affected brother. Pallister-Hall syndrome [Iafolla et al., 19891may resemble SLOS type11in most extracranial manifestations [Donnai et al., 19871. Especially the presence of a hypothalamic hamartoblastoma in Pallister-Hall syndrome is sufficient for most authors to consider the 2 as separate entities. Several authors have coined the term “pseudotrisomy 13 syndrome” for the presently described disorder [Cohen and Gorlin, 19911. Although the phenotype in the patients resembles that found in trisomy 13, we prefer not to use this term because it suggests an etiological relationship with this chromosomal abnormality, while there is at present no real clue for such a relationship. We suggest the use of the descriptive name “autosomal recessive holoprosencephaly,heart defect, and postaxial polydactyly.”The occurrence of the syndrome in 3 pairs of sibs, and the consanguinity in 3 instances make this autosomal recessive pattern of inheritance likely.

ACKNOWLEDGMENTS We thank Dr. A. E. Becker (Amsterdam)for comments on the cardiac autopsy, Drs. M. M. Cohen, Jr. (Halifax) and R. J. Gorlin (Minneapolis) for making their excellent paper available to us prior to publication, and Dr. P. Meinecke (Hamburg) for critical review of the manuscript.

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REFERENCES

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Familial holoprosencephaly, heart defects, and polydactyly.

We describe a pair of sibs with microcephaly, hypoplastic nose, cleft lip/palate, a complicated Fallot-like cardiac defect, and holoprosencephaly and ...
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