An update on the holoprosencephalic disorders

November 1982

The Journal o f P E D I A T R I C S

865

An update on the holoprosencephalic disorders Holoprosencephaly is an etiologically heterogeneous condition. Recently a number of new causes have come to light, several syndromes have been delineated or partially delineated, and a few associations have become apparent. This article updates the nosology of human holoprosencephaly.

M . Michael Cohen, Jr., D . M . D . , Ph.D., H a l i f a x , N . S . , C a n a d a

HOLOPROSENCEPHALY is a developmental field defect in which impaired cleavage of the embryonic forebrain is the basic feature. The prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telencephalon and diencephalon, and horizontally into olfactory and optic bulbs. The condition can be graded according to the degree of severity as alobar, semilobar, or lobar holoprosencephaly. Various gradations of facial dysmorphism commonly associated with holoprosencephaly include cyclopia, ethmocephaly, cebocephaly, premaxillary agenesis, and less severe facial dysmorphism. Holoprosencephaly has been reviewed extensively) -4The condition is known to be etiologically heterogeneous, and in recent years a number of new causes have come to light, several syndromes have been delineated or partially delineated, and some associations have become apparent. This article updates the nosology of human holoprosencephaly. Disorders associated with holoprosencephaly, including conditions with absent olfactory tracts and bulbs (arhinencephaly), are summarized in the Table. Absence of the corpus callosum may or may not be part of the holoprosencephalic spectrum, depending on a variety of factors: ,6 Many conditions with absence of the corpus callosum are discussed eisewhere 7 but are omitted from the Table unless other anomalies consistent with holoprosencephaly are present. Holoprosencephaly is usually sporadic, and in the overwhelming majority of instances the cause is unknown. Most cases are not associated with chromosomal aberrations, nor do they seem to represent monogenic syndromes. Of the chromosomal causes of holoprosencephaly, trisomy From the Division of Oral Biology, Faculty of Dentistry and Department of Pediatrics, Faculty of Medicine, Dalhousie University. Reprint address: M. Michael Cohen, Jr., D.M.D., Dalhousie University, Halifax, N.S., Canada B3H 3,15.

0022-3476/82/110865+05500.50/0

9 1982 The C. V. Mosby Co.

Fig. 1. Left. Holoprosencephaly, encephalocele, and cyclopia. (From Cohen MM, Strom DF, and Capraro VJ: Clin Genet 3:249, !972.) Right, Holoproseneephaly, anencephaly, and cebocephaly. (Courtesy of R. J. Lemire, Seattle.)

13 occurs most commonly, and 18p- and 13q- karotypes With holoprosencephaly are well known but f a r less common. The variety of unusual karyotypes reported in association with holoprosencephaly (Table) permits the prediction that other unusual karyotypes with holoprosencephaly will be observed in the future. Of the monogenic causes of holoprosencephaly, Meckel syndrome is the most well known. Another condition, the autosomal-dominant form of holoprosencephaly, has not been sufficiently appreciated. Some individuals are so mildly affected that the condition may go undetected; features include mild mierocephaly, mild mental deficiency, mild ocular hypotelorism, anosmia, hyposmia, mild midfac e deficiency, or single maxillary central incisor: Various abnormalities associated with holoprosencephaly such as anencephaly, encephalocele, and DiGeorge

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The Journal o f Pediatrics November 1982

Table. Conditions associated with holoprosencephaly Condition

Chromosomal Trisomy 13

13q-

18pTrisomy 18 Trisomy 21 Triploidy 47,XX, +C 46,XY/47,XY,+frag 47,XY,+B 46,XX,t(3p;?) Partial monosomy 22pter-~ql 1 Partial trisomy lq 46,XY/45,XY,-G Monogenic holoprosencephaly Meckel syndrome

Comments

Holoprosencephaly common, full spectrum of facial dysmorphism; most common chromosomal syndrome with holoprosencephaly Holoprosencephaly common, semilobar or lobar holoprosencephaly without extremely severe facial dysmorphism Holoprosencephaly uncommon, full spectrum of facial dysmorphism Ho!oprosencephaly uncommon Holoprosencephaly rare Holoprosencephaly uncommon - -

3

21

22 23, 24 25 26 27

- -

28

- -

29

- -

30

- -

31

HoloProsencephaly uncommon

32 33

- -

May have holoprosencephalywith median or lateral cleft lip~autosomal-recessiveinheritance Autosomal-recessiveholoprosenFull spectrum of facial dysmorphism; may vary within families cephaly Autosomal-dominant holoprosen- Incomplete penetrance with remarkably variable expressivity; mildly affected individuals may have only cephaly slight ocular hypotelorism, anosmia, hyposmia, or single maxillary central incisor Agnathia-holoprosencephaly Variable expression of both holoprosencephalyand agnathia; autosomal-recessiveinheritance likely Holoprosencephaly-endocrine dys- Holoprosencephaly, facial clefts, genital hypoplasia, genesis endocrine dysgenesis;autosomal-recessiveinheritance likely Monogeoic arhinencephaly Kallmann syndrome Anosmia, hypogonadotropic hypogonadism, various other anomalies; X-linked or male-limited autosoreal-dominant form; etiologically heterogeneous Isolated arhinencephaly X-linked and autosomal-dominant forms

syndrome4'8'9 have been emphasized recently (Fig. 1). Although environmentally induced holoprosencephaly has been observed in a variety of experimental animals,4 further epidemiologic studies are necessary to prove or disprove various environmental causes of holoprosencephaly in humans. Maternal diabetes: viral infection, toxoplasmosis, and various drugs, including phenytoin and salicylates, have been suggested as having possible teratogenic effects in humans:, t0 Relationships between a number of intriguing conditions and holoprosencephaly deserve further study. The finding of a single maxillary central incisor in association with hypopituitarism has been reported in several sporadic cases, u If it could be established that the hypopituitarism had a hypothalamic basis, such patients might represent

Reference

34 3,4

Personal communication (R. M. Pauli) Personal communication (M. L. Begleiter, and D. J. Harris) 36-39

36

the mild end of the holoprosencephalic spectrum. The finding of three affected sibsntwo with classic holoprosencephaly and facial dysmorphism and one with hypopituitarism and an essentially normal facelZ--suggests that hypopituitarism may be the sole manifestation in some patients with holoprosencephaly. The association of cleft lip or cleft palate with growth hormone deficiencyt3 is also suggestive of a holoprosencephalic microform. The relationship between holoprosencephaly and septooptic dysplasia ~4and Rieger syndrome ~5remains speculative. Several conditions may simulate holoprosencephaly. In the Binder syndrome, t6 for example, the midface deficiency and nasal configuration are reminiscent of an "arhinencephaloid face." Occasionally, isolated median cleft lip may occur without holoprosencephaly.17 Martin et al TM re-

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Update on holoprosencephalic disorders

867

Table--cont'd Condition

Comments

Reference

Monogenic arhinencephaly--cont'd

Perrin syndrome V~radi syndrome

Campomelic dysplasia

Radiohumeral synostosis syndrome Unknown genesis Hall-Pallister syndrome Aprosencephaly syndrome Fitch syndrome

COH syndrome Associations Holoprosencephaly/ anencephaly Holoprosencephaly/ encephalocele Holoprosencephaly/ DiGeorge syndrome

Anosmia, mental deficiency, hypogonadism, congenital ichthyosis; X-linked recessive inheritance Arhinencephaly, cleft lip-palate, lingual nodule, growth deficiency, psychomotor retardation, duplicated halluces, supernumerary fingers, congenital heart defeet, cryptorchidism; autosomal-recessive inheritance Macrodolichocephaly, slitlike wide-set eyes, flat nasal bridge, long philtrum, mierognathia, small mouth, cleft palate, abnormal ears, bell-shaped chest, short bowed femora and tibiae, various roentgenographie abnormalities, pretibial skin dimples, talipes equinovarus, hallux deviation, mild brachydaetyly, hypotonia, arhinencephaly (18%); autosomal-recessive inheritance most likely Anosmia, Robin sequence, radiohumeral synostosis; autosomal-dominant inheritance most likely

40

Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, postaxial polydactyly, other anomalies including holoprosencephaly (1/6) Aprosencephaly with facial features of holoprosencephaly, radial aplasia, genital anomalies Arhinencephaly, absent corpus cal[osum, hydrocephaly, absent left hemidiaphragm, ventricular septal defect, absent fifth fingernails Arhinencephaly, polymicrogyria, hydrocephaly, cloverleaf skull, duplication of thumb, micropenis, bifid scrotum

43

41

42

Personal observation (J. W. Hanson and M. M. Cohen, Jr.)

44 46

46

Observed with cyclopia, cebocephaly, median cleft lip, lateral cleft lip Observed with Meckel syndrome and cyelopia with 18pArhinencephaly observed in 3 of 25 autopsies with Di George syndrome

ported an autosomal-dominant midline clefting syndrome resembling holoprosencephaly. Features included mental deficiency, microcephaly, large external ears, cleft lip, anterior cleft palate, absence of central and lateral incisors, absence of the premaxilla, ocular hypotelorism, downslanting palpebral fissures, and skeletal anomalies, notably clubfoot and spinal anomalies. Another condition unrelated to holoprosencephaly is accessory proboscis in the presence of two nostrils, representing the abnormal embryonic development of a supernumerary nasal placode? The severe facial dysmorphism of cyclopia, ethmocephaly, cebocephaly, and premaxillary agenesis is almost always, but not in every instance, pathognomonic of holoprosencephaly. However, some patients may have mild involvement such as mild ocular hypotelorism or even hypertelorism in addition to the various features seen in the

autosomal-dominant form of the disorder. Because holoprosencePhaly.with facial dysmorphism is frequently part of a broader pattern of defects, a careful search should be carried out for other anomalies. Any patient suspected of having holoprosencephaly by physical examination, neurologic observation, and neurologic testing is a candidate for computed tomographyJ 9 In all patients with holoprosencepbaly, a banded chromosome study should be done. The family history is extremely important, not only for obviously affected members but for individuals who might have a very mild expression of the disorder. A history of mental deficiency, short stature, or endocrine abnormalities in a family is provocative and should be carefully investigated. When holoprosencephaly occurs with severe facial dysmorphism and associated anomalies, the condition is likely

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The Journal o f Pediatrics November 1982

Mild ~11 Facial malformations and/or I ~ Severe neurologic abnormalities Associated anomalies Family history Laboratory tests

~ ' ~ f

otheranomalies

Monogen-ic (except 13q-)

Severefacial J ~Associated //isolated "~nomalies

1,.,/ Sporadic, monogenic

"Nk Chromosomal(except Meckel syndrome), sporadic

1 I.

12.

13.

14.

15.

Fig. 2. Flow chart indicating diagnostic considerations in holoprosencephaly. 16. to be chromosomal. T h e only known monogenic syndrome with severe facial d y s m o r p h i s m together with associated anomalies is Meckel syndrome (Fig. 2). For a sporadic occurrence of n o n c h r o m o s o m a l severe holoprosencephaly, the recurrence risk is approximately 6%. 20 W h e n facebrain dysmorphism is relatively mild, the condition is likely to be monogenic, except for the 13q- syndrome.

17.

18.

19.

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other anomalies following maternal ingestion of salicylates, J PEDIATR 96:1069, 1980. Rappaport EB, Ulstrom RA, Gorlin R J, Lucky AW, Colle E, and Miser J: Solitary maxillary central incisor and short stature, J PEDIATR 91:924, 1977. Romshe C, and Sotos JF: Hypothalamic-pituitary dysfunction in siblings of patients with holoprosencephaly, J PEDIATR 83:1088, 1973. Rudman D, Davis GT, Priest JH, Patterson JH, Kutnzr MH, Kutner MH, Heymsfield SB, and Bethel RA: Prevalence of growth hormone deficiency in children with cleft lip or palate, J PEDIATR 93:378, 1978. Hoyt WF, Kaplan SL, Grumbach MM, and Glaser JS: Septo-optic dysplasia and pituitary dwarfism, Lancet 1:893, 1970. Sadeghi-Nejad A, and Senior B: Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome), J PEDIATR 85:644, 1974. Gorlin R J, Pindborg J J, and Cohen MM Jr: Syndromes of the head and neck, ed. 2, New York, 1976, McGraw-Hill Book Company. Ben-Hur N, Asher H, and Musseri M: An unusual case of median cleft lip with orbital hypotelorism: A missing link in the classification, Cleft Palate J 15:365,1978. Martin AO, Perrin JCS, Muir WA, Rudi E, and Schafer IA: An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly, Clin Genet 12:65, 1977. Byrd SE, Harwood-Nash DC, Fitz CR, and Rogovitz DM: Computed tomography evaluation of holoprosencephaly in infants and children, J Comput Assist Tomogr 1:456, 1977. Roach E, DeMyer W, Palmer K, Connelly M, and Merritt A: Holoprosencephaly: Birth data, genetic and demographic analysis of 30 families, Birth Defects 11:294, 1975. Orbeli D J, Lurie IW, and Goroshenko JL: The syndrome associated with the partial D-monosomy: Case report and review, Hum Genet 13:296, 1971. de Grouchy J: The 18p-, 18q- and 18r syndromes, Birth Defects 5:73, 1969. Hunter AGW, Ray M, and Langston C: Cebocephaly in an infant with trisomy 18, J Med Genet 14:291, t977. Lang AP, Schlager FM, and Gardner HL: Trisomy 18 and cyclopia, Teratology 14:195, 1976. Pi SY, Fineman RM, Wing SD, Grunnet M, and Chan G: Brief clinical reports: Holoprosencephaly in a Down syndrome child, AM J Med Genet 5:201, 1980. Zergollern L, Drazancic A, Damjanov I, Hitrec V, and Gorecan V: A liveborn infant with triploidy (69, XXX), Z Kinderheilk 112:293, 1972. Holmes LB, Driscoll S, and Atkins L: Genetic heterogeneity of cebocephaly, J Med Genet 11:35, 1974. Pfitzer P, and M~intefering H: Cyclopism as a hereditary malformation, Nature 217:1071, 1968. Boub J, and Albert DM: The eyes of embryos with chromosomal abnormalities, Am J Ophthalmol 78:167, 1974. Hsia YE, Appadorai V, Breg WR, and Howard RO: Chromosomal abnormality (46,XX,3p+) in a case of the Meckel syndrome, Birth Defects 10:19, 1974. Back E, Stier R, BShm N, Adlung A, and Hameister H: Partial monosomy 22 pter---~ql I in a newborn with the clinical features of trisomy 13 syndrome, Ann Genet 23:244, 1980. Gardner R, McCranor H, Parslow M, and Veale A: Are lq+ chromosomes harmless? Clin Genet 6:383, 1974.

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33. Cohen MM: Chromosomal mosaicism associated with a case of cyclopia, J PEDIATR 69:793, 1966. 34. Hsia YE, Bratu M, and Herbordt A: Genetics of the Meckel syndrome (dyseneephalia splanchnoeystica), Pediatrics 48:237-247, 1971. 35. Fraser FC, and Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or "Maybe there is a malformation syndrome with at least one constant anomaly," Am J Med Genet 9:67, 1981. 36. Wegenke JD, Uehling DT, Wear JB Jr, Gordon ES, Bargman JG, Deacon JSR, Herrmann JPR, and Opitz JM: Familial Kallmann syndrome with unilateral renal aplasia, Int J Clin Genet 7:368, 1975. 37. Friedman N, Levitsky LL, Edidin DV, and Weiss E: Choanal atresia and associated anomalies, J PEDIATR 96:1123, 1980. 38. Merriam GR, Beitins 1Z, and Bode HH: Father-to-son transmission of hypogonadism with anosmia, Am J Dis Child 131:1216, 1977. 39. Rosenberg SM, and Riddick DH: Dynamic pituitary testing in a female with Kallmann's syndrome and associated cardiac anomaly, Obstet Gyneeol 48:230, 1976. 40. Perrin JCS, Idemoto JY, Sotos JF, Maurer WF, and Steinberg AG: X-linked syndrome of congenital ichthyosis, hypo-

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gonadism, mental retardation and anosmia, Birth Defects 7:267, 1976. V~radi V, Szab6 L, and Papp Z: Syndrome of polydactyly, cleft lip/palate or lingual lump, and psychomotor retardation in endogamie gypsies, J Med Genet 17:119, 1980. Hall BD, and Spranger JW: Campomelic dysplasia: Further elucidation of a distinct entity, Am J Dis Child 134:285, 1980. Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke P J, and Reed SD: Congenital hypothalmic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly: A new syndrome? I. Clinical, causal, and pathogenetic considerations, Am J Med Genet 7:47, 1980. Lurle IW, Nedzved MK, Lazjuk l, Kirillova IA, and Cherstvoy ED: Brief clinical reports: Aprosencephaly-atelencephaly and the aprosencephaly (XK) syndrome, Am J Med Genet 3:303, 1979. Fitch N, Srolovitz H, Robitaille Y, and Guttman F: Absent left hemidiapbragm, arhinencephaly, and cardiac malformations, J Med Genet 15:399, 1978. Cohen MM Jr: The child with multiple birth defects, New York, 1982, Raven Press.