Alobar Holoprosencephaly: Report of Two Cases with Unusual
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Alobar Holoprosencephaly: Report of Two Cases with Unusual
Case Report 700 Alobar Holoprosencephaly: Report of Two Cases with Unusual Findings Li-Hsiung Chang, MD Holoprosencephaly, a disorder resulting from failure of cleavage or incomplete differentiation of the forebrain structures at various levels or to various degrees, is related to hereditary factors, chromosomal anomalies, cytogenetic abnormalities, and environmental teratogenic factors. We report on 2 cases of alobar holoprosencephaly, with similar physical findings, including microcephaly, microphthalmia, cebocephalus, choanal atresia, pseudo cleft palate, distended abdomen, and acrocyanosis. The brain echogram of these 2 patients demonstrated fused thalami and a single large U-shaped ventricular cavity. Chromosome studies of these 2 patients were normal. The findings of the autopsies confirmed the clinical presentations. One of our cases had a clinical picture similar to that of holoprosencephalypolydactyly syndrome. The other had the rare anatomical finding of a polylobuated spleen. Because of the poor prognosis of alobar holoprosencephaly, early prenatal diagnosis is recommended. (Chang Gung Med J 2003;26:700-6) Key words: alobar holoprosencephaly, polydactyly, polysplenia. I n 1963, Demyer and Zeman(1) proposed the term holoprosencephaly which is a disorder resulting from failure of septation, cleavage, or differentiation of the midline forebrain structures at various levels or to various degrees. Defects in development of the midfacial region frequently coexist. The disease affects both components of the forebrain: the telencephalon and the diencephalon. Demyer et al. divided the pathological characteristics of the forebrain into 4 categories: lobar (presence of an interhemispheric fissure but the cingulate gyrus and the lateral ventricles are fused, and there is no septum pellucidum), semilobar (posterior partial formation of the interhemispheric fissure, with only a single ventricle), variant (heterotopic gray matter), and alobar (absence of the interhemispheric fissure, falx cerebri, the third ventricle, and fused thalami, and often absence of neurohypophysis and olfactory tracts) ones according to the graded degrees of failed differentiation.(1) The various holoprosencephalic abnormalities of the face include cyclopia, proboscis, ethmocephalus, cebocephaly, premaxilla agenesis, median cleft palate/lip, and other less-severe facial dysmorphism. Holoprosencephaly is an extremely heterogeneous disease, whose origin can be related to chromosomal, monogenic, and environmental teratogenic factors and which may be associated with other anomalies. We present the clinical, cytogenetic, and pathological findings of 2 newborn babies. One who possessed preaxial polydactyly had clinical presentations similar to those of holoprosencephaly-polydactyly syndrome; the other had the rare finding of a polylobulated spleen. From the Department of Pediatrics, Taichung Hospital, Department of Health, Executive Yuan, Taichung. Received: Sep. 25, 2002; Accepted: Mar. 4, 2003 Address for reprints: Dr. Li-Hsiung Chang, Department of Pediatrics, Taichung Hospital, Department of Health, Executive Yuan. 199, San-Min Road, Sec. 1, Taichung 400, Taiwan, R.O.C. Tel.: 886-4-22294411 ext. 2276; Fax: 886-4-22585806; E-mail: [email protected] Li-Hsiung Chang Alobar holoprosencephaly CASE REPORT Case 1 This was the second pregnancy of non-consanguineous parents, aged 33 and 35 years, respectively. A C 701 The first pregnancy of the mother had ended with a spontaneous abortion. There was a history of neither hereditary disease nor chromosome disorders in either family. The mother had received no regular B D Fig. 1 Case 1. (A) Anterior view of the face; (B) brain sonogram; (C) single large ventricle without septation; and (D) polylobulated spleen. Chang Gung Med J Vol. 26 No. 9 September 2003 702 Li-Hsiung Chang Alobar holoprosencephaly prenatal checkups, including ultrasound examination, during the entire course of the pregnancy; hence, no diagnosis was made during the prenatal stage. In the 38th week of gestational age, a female baby weighing 3200 g was born via cesarean section due to premature rupture of the membrane for 8 hours. General cyanosis and delayed initial crying occurred immediately after delivery. The Apgar scores were 5 at 1 min and 7 at 5 min. She was immediately admitted to the neonatal intensive care unit. Physical examinations showed lethargy, microcephaly (less than the 3rd percentile), short stature (less than the 3rd percentile), microphthalmia, hypotelorism, cebocephalus, choanal atresia, pseudo cleft palate, a moderately distended abdomen, and acrocyanosis. The newborn died on the third day of life. A brain A C echogram performed on the first day of admission showed a fused thalamus and a single large U-shaped ventricular cavity. The chromosomal analysis showed a 46,XX, normal karyotype. An autopsy was performed with the parents' consent. The abnormal findings of the autopsy included: (1) a single large ventricle with an opening to the posterior part of the brain, (2) the absence of olfactory and optic nerves, (3) dysgenesis of the hypopituitary, thyroid, and adrenal glands, (4) choanal atresia, (5) no lobulation of the left lung, and (6) polylobulation of the spleen. Case 2 This female baby was born to 34- and 31-yearold, non-consanguineous parents who had suffered B D Fig. 2 Case 2. (A) Anterior view of the face; (B) brain sonogram; (C) preaxillary polydactyly; and (D) single large ventricle without septation. Chang Gung Med J Vol. 26 No. 9 September 2003 Li-Hsiung Chang Alobar holoprosencephaly from infertility for 3 years. The primigravida was transferred to our obstetric department for confirmation of hydrocephalus which was suspected during the last month of pregnancy by local medical clinics. Fetal ultrasonography at 37 weeks of gestation revealed oligohydramnios, microcephaly, a single large ventricle, a fused thalamus, and hypotelorism. A tentative prenatal diagnosis of alobar holoprosencephaly was made. A child weighing 2900 g was born at 38 weeks of gestation by cesarean section due to breech presentation. A delay of initial crying was found after delivery. The Apgar scores were 4 at 1 min and 6 at 5 min. There were similar abnormal physical findings as those of case 1, including microcephaly, microphalmia, hypotelorism, cebocephalus, a pseudo cleft palate, and choanal atresia; preaxial polydactyly of the left hand was an additional finding. The results of a postnatal brain echogram were the same as those of the prenatal stage. She died at 30 hours of age. The karyotype of the patient was 46,XX. The abnormal findings by autopsy included: (1) a single large ventricle with an opening to the posterior part of the brain and a fused thalamus, (2) the absence of olfactory and optic nerves, (3) dysgenesis of the hypopituitary, thyroid, and adrenal glands, (4) choanal atresia, and (5) polydactyly. DISCUSSION During the third week of embryonic life, the prechordal mesoderm migrates into the area prior to the notochord and affects midline facial development; hence, before 4 weeks of embryonic age, the varying degrees of loss or disruption in the development of prechordal mesoderm cause abnormal forebrain development and midfacial defects.(2) Holoprosencephaly, the most common structural anomaly of the developing forebrain and midface in humans, is a disorder in which the cephalic neural tube fails to develop and does not divide into right and left lobes. Holoprosencephalon is the term used to describe a single, unpaired forebrain. The epidemiology of holoprosencephaly was poorly described before, partly due to the inclusion of only small case numbers and there being no basal population; on the other hand, there is marked natural loss of the fetus, while milder forms may go unrecognized. Consequently, the prevalence rate differs in various study groups. During early embryo- 703 genesis, it is about 1 in 250; due to the high rate of spontaneous abortion, the prevalence rate in live births ranges from 1: 14,736 to 1: 26,730.(3) The first population-based survey of holoprosencephaly prevalence provided by Bullen et al. representing the total prevalence (including pregnancy termination) was 1.2 cases per 10,000 registered births, and the birth prevalence (affected live births and stillbirths at > 24 weeks' gestation) was 0.49 cases per 10,000 births. The etiology of holoprosencephaly indicates interactions with both genetic and environmental factors, including chromosomal anomalies, gene rearrangements, mendelian mutations, and teratogens, and it can usually be determined. Although it is extremely heterogeneous, there may be a common final pathway for the abnormal development of the forebrain and face. The majority of holoprosencephaly cases are sporadic; cases of familial holoprosencephaly are reported to be autosomal dominant, autosomal recessive, or X-linked in inheritance. Nearly 50% of all holoprosencephaly cases have cytogenetic abnormalities, and approximately 18%-25% of patients of holoprosencephaly have a documented monogenic syndrome.(4,5) To the present, there are at least 12 known loci which may contain genes critical for normal brain development on 11 chromosomes. Trisomy 13 is the most commonly identified cause; others include trisomy 18, HPE1(21q22.3), HPE2(2p21,SIX3), HPE3(7q36, SHH,SonicHedgehog), HPE4(18p11.3,TGIF), (6) HPE5(13q32,ZIC2), HPE6(3p24-pter), HPE7 (13q12-q14), HPE8(14q13), HPE9(20p13), HPE10 (1q42-qter), HPE11(5p), HPE12(6q26-qter), (7) t(7;13)(q21.2;q33), 3q22 deletion,13q33, q34 or 35qter deletion, 7q36-qter deletion, and 14q22 deletion,del(14) (q11.1q13).(8) Environmental teratogens reported to induce holoprosencephaly include maternal diabetics (with a reported 200-fold increase in the incidence of holoprosencephaly in infants of diabetic mothers over infants of non-diabetic mothers), (9) steroid alkaloids, thanol, and retinoic acid. (10) Syndromatic associations include Martin syndrome, Steinfeld syndrome, CHARGE association, MeckelGruber syndrome, Kallmann syndrome, HallPallister syndrome, Vasidi syndrome,(11) Smith-LemliOpitz syndrome, holoprosencephaly-polydactyly syndrome, (12) and Rubenstein-Taybi syndrome. Associated abnormalities include microcephaly, Chang Gung Med J Vol. 26 No. 9 September 2003 704 Li-Hsiung Chang Alobar holoprosencephaly hydrocephalus, agenesis of the corpus callosum, posterior fossa abnormality, cerebellar vermis aplasia, myelomingocele, absence of an olfactory bulb, a cleft lip/palate, adrenal hypoplasia, renal dysplasia, renal cysts, omphalocele, cardiovascular malformations, intestinal abnormalities, club foot, sirenomelia, (13) spina bifida, and endocrinopathies (pituitary gland dysplasia, growth hormone deficiency, and diabetes insipidus).(14) Knowing the etiologies of holoprosencephaly is important for establishing the risk of recurrence. One of our cases with a normal karyotype, who possessed polydactyly, and adrenal and thyroid gland dysgenesis, is compatible with the clinical picture of holoprosencephaly-polydactyly syndrome, a moreneutral term recommended by Verloes et al.(12) to substitute for the previous term of pseudotrisomy 13 syndrome suggested by Hewitt et al.(15) The characteristics of the polydactyly in our patient was of the preaxial type, in comparison to the postaxial polydactyly in all reported cases of holoprosencephalypolydactyly syndrome. Most cases of holoprosencephaly-polydactyly syndrome are sporadic, but autosomal recessive and autosomal dominant modes of inheritance have also been reported. The hypothesis is that a chromosomal rearrangement or duplication occurs between 13q31 and 13q34. In 1991, Raoul suggested the use of the descriptive name of autosomal recessive holoprosencephaly, heart defect, and postaxial polydactyly syndrome. (16) In 1993, Lurie and Wulfsberg suggested the use of an eponymic name, such as the Cohen-Gorlin syndrome, because they found that neither holoprosencephaly nor polydactyly was an obligatory manifestation of this disease entity.(17) One of our patients had polysplenia which is a rare finding in holoprosencephaly cases. The phenotypic expression of holoprosencephaly varies widely. "The face predicts the brain" as recommended by DeMyer et al. in 1963(1) is correct in about 70%-80% of cases, but not in all children with holoprosencephaly. The craniofacial anomalies include cyclopia (a single eye or partially divided eyes in a single orbit with a proboscis above the eye), ethmocephaly (severe hypotelorism and a proboscis between the eyes), cebocephaly (hypotelorism, a single nostril, and a blind-ended nose), premaxillary agenesis, arhinencephalia (the absence of olfactory bulbs and tracts), agenesis of the Chang Gung Med J Vol. 26 No. 9 September 2003 corpus callosum. Facial-only phenotypes include midface hypoplasia, hypotelorism, coloboma, microphthalmia, unilateral or bilateral clefts, solitary central incisor and/or pyriform aperture stenosis, hypotelorism, the absence of nasal bones or a flat nose, and the absence of the upper lip midline frenulum. Milder forms may be unrecognized if imaging studies of the brain are not arranged. Patients with severe forms of holoprosencephaly usually die during the first year of life.(19) Both of our cases who were diagnosed to be of the alobar type expired within 3 days after birth. The less-severe forms, i.e., semilobar or lobar holoprosencephaly, may allow longer life spans if other associated abnormalities are not life threatening. But all survivors have the inability to smell, developmental delay, profound intellectual impairment, and seizures.(19) Other problems include (1) increased muscle tone to the point of spasticity, poor control of muscles, and contractures; (2) fluctuating behavior between calmness and irritability, with sudden changes in mood; (3) hoarse, barking, or a highpitched voice; (4) difficulty with swallowing, choking spells and gagging during feedings, spitting up, frank vomiting, risk of aspiration, and constipation; (5) growth delays, (6) sleep disturbances; (7) periodic brain stem and/or hypothalamus dysfunction with irregular breathing, heart rhythm, and heart rate, and unstable temperature control; and (8) pituitary and/or thyroid gland dysfunction.(18) The cause of death is usually abnormal brain stem function, especially superimposed with infection, diabetes insipidus causing severe dehydration, or intractable seizures. Early detection by sonography offers a better and earlier diagnostic procedure than amniocentesis. The earliest gestational age at the time of diagnosis was 14 weeks. Because of the short life span and ominous outcome in all patients with alobar holoprosencephaly, genetic counseling and prenatal diagnosis by ultrasound (transabdominal or transvaginal scanning) are of great importance for early detection and allows earlier termination of the pregnancy.(19) In summary, we report on 2 cases of alobar holoprosencephaly with the special findings of polysplenia in case 1 and preaxial polydactyly in case 2. The variety of clinical pictures and the complexity of genetics in holoprosencephaly require further investigations in clinical, radiological, pathological, genetic, embryological, and teratogenic fields. Li-Hsiung Chang Alobar holoprosencephaly REFERENCES 1. DeMyer W, Zeman W, Palmer CG. The face predicts the brain: diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 1963;34:256-63. 2. Muenke M, Beachy PA. Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 2000;10:262-9. 3. Cohen MM. Perspectives on holoprosencephaly. Part I. Epidemiology, genetics and syndromology. Teratology 1989;40:211-35. 4. Croen LA, Shaw GM, Lammer EJ. Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet 1996;64:465-72. 5. Olsen CL, Hughes JP, Youngblood LG, Sharpe-Stimac M. The epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State,19841989. Am J Med Genet 1997;73:217-26. 6. Frezal J, Schinzel A. Report on the Committee on clinical disorders, chromosome aberrations and uniparental disomy. Cytogenet Cell Genet 1991;58:986-1052. 7. Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat 2000;16:99-108. 8. 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Cebocephaly, alobar holoprosencephaly, spina bifida, and sirenomelia in a stillbirth. J Med Genet 1997;34:252-5. Traggiai C, Stanhope R. Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr 2002;140:252-5. Hewitt BG, Seller MJ, Bennet CP, Maxwell DM. Holoprosencephaly, polydactyly and normal chromosomes: pseudotrisomy 13? Clin Genet 1989;36:141-3. Hennekam RC, van Noort G, de la Fuente AA. Familial holoprosencephaly, heart defects, and polydactyly. Am J Med Genet 1991;41:258-62. Lurie IW, Wulfsberg EA. Holoprosencephaly-polydactyly (pseudotrisomy 13) syndrome: expansion of the Phenotypic Spectrum. Am J Med Genet 1993;47:405-9. Barr M Jr, Cohen MM Jr. Holoprosen-cephaly survival and performance. Am J Med Genet 1999;89:116-20. Bronshtein M, Wiener Z. Early transvaginal sonographic diagnosis of alobar holoprosencephaly. Prenat Diagn 1991;11:459-64. 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