Alobar Holoprosencephaly Research Articles

Cyclopia: isolated and with agnathia–otocephaly complex

Cyclopia is a rare form of lethal holoprosencephaly (HPE) due to incomplete cleavage of prosencephalon during embryogenesis, leading to failure of the orbits of the eye to divide into two...

Prenatal diagnosis of holoprosencephaly associated with Smith–Lemli–Opitz syndrome (SLOS) in a 46,XX fetus

ObjectiveTo show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith–Lemli–Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. Case reportA 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal – 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. ConclusionThe differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.

Impact of holoprosencephaly, exomphalos, megacystis and increased nuchal translucency on first-trimester screening for chromosomal abnormalities.

To examine the prevalence of alobar holoprosencephaly, exomphalos, megacystis and nuchal translucency thickness (NT) ≥ 3.5 mm, the incidence and types of chromosomal abnormalities associated with these conditions and their overall impact on the rate of invasive testing and performance of screening at 11-14 weeks. This was a prospective screening study for trisomies 21, 18 and 13 by the first-trimester combined test at three maternity units in England. In the study population of 108 982 singleton pregnancies, 870 (0.8%) had abnormal karyotype, including 654 (75.2%) with trisomies 21, 18 or 13 and 216 (24.8%) with other chromosomal abnormalities. The prevalence of alobar holoprosencephaly, exomphalos, megacystis and NT ≥ 3.5 mm was 1 in 2945, 1 in 419, 1 in 1345 and 1 in 119, respectively. Chromosomal abnormalities were observed in 78.4% of cases of holoprosencephaly, 40.8% of exomphalos, 18.5% of megacystis and 48.5% of those with NT ≥ 3.5 mm. The most common chromosomal abnormality associated with holoprosencephaly was trisomy 13, with exomphalos and megacystis was trisomy 18 and with increased NT was trisomy 21. Fetal karyotyping of cases with major fetal defects or increased NT would potentially detect 57% of all chromosomal abnormalities at an invasive testing rate of 1.1%. Major fetal defects and increased NT at 11-13 weeks' gestation are associated with a high risk of chromosomal abnormalities and merit invasive fetal testing. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Holoprosencephaly.

Holoprosencephaly (HPE) is a brain malformation resulting from failure of prosencephalon (the forebrain of the embryo) to divide into two distinct cerebral hemispheres. It is the most common brain malformation with an incidence of 1:250 during embryogenesis and 1:16,000 among live births.1 HPE has four subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly).2 Alobar holoprosencephaly is the most severe form, and as the name implies, there is no separation of the cerebral hemispheres. In semilobar holoprosencephaly, the cerebral hemispheres separate posteriorly, however are fused anteriorly. Lobar holoprosencephaly is characterized by almost complete separation of the cerebral hemispheres. Syntelencephaly results from failure of separation of posterior frontal and parietal lobes. Since both the forebrain and midface arise from the prechordal mesoderm, majority of patients with HPE also manifest craniofacial abnormalities such as microcephaly, microphthalmia, cleft lip and palate, flat nose, absent nasal bridge, and cyclopia. Multiple genetic and environmental factors are involved in the pathogenesis of HPE. Maternal diabetes mellitus is a well-known risk factor.3 Exposure to retinoic acid, diphenylhydantoin, aspirin, misoprostol, methotrexate, cholesterol-lowering agents and alcohol during pregnancy have been associated with HPE.4-9 Other environmental factors include TORCH infections during early pregnancy.1 Genetic abnormalities associated with HPE include trisomy 13, trisomy 18, and triploidy.10,11 Syndromic association of HPE includes, but is not limited to Smith-Lemli-Opitz syndrome, Genoa syndrome, Meckel-Gruber syndrome, Lambotte syndrome, Pallister-Hall syndrome, Steinfeld syndrome, caudal dysgenesis and Aicardi syndrome.12-19 Mutations in SHH, ZIC2, SIX3, and TGIF genes have been implicated in non-syndrome associated HPE.20 Central nervous system abnormalities are identified on routine prenatal imaging and etiologic diagnosis can be done by prenatal or postnatal karyotype and testing for known gene mutations. Sub classification is based on MRI findings or autopsy findings if one is requested. Infants who survive have a myriad of clinical presentation. Some of the common physical findings include spasticity, hypotonia, choreoathetosis and dystonia. Infantile spasms and seizures are common. Feeding difficulties, gastroesophageal reflux, and malnutrition occur commonly. Other problems include temperature dysregulation and respiratory tract infections. Death usually occurs due to brainstem dysfunction or manifestation and complications of associated syndromes. Treatment is mainly supportive. Prognosis depends upon subtype and associated syndrome.21 Those with alobar type die within days of birth.22 Around 50% with the isolated semilobar form survive beyond 1 year.22 Recurrence risk in subsequent pregnancies is high in established cases of parental carrier state and is low if the genetic abnormalities occur de novo.23,24 Figure 1 refers to gross appearance of brain in a 7-hour old female infant born to a 41-year old G1 P0 lady with limited prenatal care, past medical history of diabetes mellitus type 2 and alcohol use during first trimester of the pregnancy. On prenatal ultrasonography, the fetus had hydrocephalous and suboptimal development of cerebral and cerebellar hemispheres. Karyotyping showed normal signal pattern for chromosomes 13, 18 and 21. Figure 1Macroscopic appearance of the brain depicting complex gyration without classical sulcal landmarks (A and B) and focal polymicrogyria (A), flattened cerebral hemispheres surrounding a single cystically dilated ventricle (C), fused right and left basal ganglia and diencephalic structures (C), unremarkable midbrain, cerebellum and medulla (D).: Pictures courtesy Dr. Ameer Hamza Autopsy findings included fetal macrosomia; craniofacial dysmorphogenesis to include hypertelorism, low set ears, cleft palate, absent nasal bridge and bossing of forehead; biventricular cardiomegaly, muscular ventricular septal defect and imperforated anus. The detailed brain examination revealed flattened frontal, temporal and occipital lobes with a rudimentary C-shaped interhemispheric fissure. The surface of the cystically dilated forebrain displayed complex gyration; however, without classical sulcal landmarks (Figure 1A and 1B). There were focal polymicrogyria patches (Figure 1A). Cortical pallium surrounded a single large cystic cavity (telencephalic vesicle) in which lateral ventricles and ventricular horns could not be discerned (Figure 1 C). At the base of cystically dilated cerebrum, there were fused right and left basal ganglia and diencephalic structures (Figure 1C). There was no corpus callosum. The midbrain, cerebellum and medulla appeared unremarkable (Figure 1D).

Antenatally diagnosed alobar holoprosencephaly: A report of two cases

Holoprosencephaly is a complex developmental abnormality of the brain arising from the failure of cleavage of the prosencephalon. The condition termed “holoprosencephaly” includes cyclopia, cebocephaly, ethmocephaly, and median cleft. We present two cases of antenatally diagnosed alobar holoprosencephaly with multiple associations, which were confirmed after termination of pregnancy. One of them had a proboscis and a single midline eye. The other had multiple facial abnormalities such as hypotelorism, median cleft lip and palate, and preauricular skin tag.

Alobar Holoprosencephaly With Cebocephaly

Holoprosencephaly (HPE) is a complex brain malformation caused by incomplete fusion of cleavage of the cerebral hemispheres and deep brain structures affecting 6 to 12:10,000 live-born infants. There are three categories of HPE ranging in severity, with alobar holoprosencephaly being the most severe, followed by semilobar holoprosencephaly, and lobar holoprosencephaly being the mildest form. Facial anomalies as well as chromosome anomalies are often associated with HPE. This case study describes a transabdominal sonographic diagnosis of alobar HPE with cebocephaly originally found at 27 weeks 3 days on a patient with no prenatal care.

Central Nervous System Anomalies Detectable in the First Trimester

ABSTRACT Prenatal diagnosis of central nervous system (CNS) congenital anomalies is possible in the second and third trimester. Earlier diagnosis is possible for some of these as the complex acranial/exencephaly/anencephaly and alobar holoprosencephaly (HPE). The knowledge of normal fetal brain development and its ultrasound images at the different weeks’ gestation, the expertise of operators, and high-resolution equipment are essential to obtain good results. The diagnosis in the first trimester of some major anomalies incompatible with extrauterine life or associated with severe handicap is useful to inform the couple, to perform additional examinations, and provide them with the option of earlier and safer pregnancy termination. For some other conditions, like agenesis of corpus callosum and hypoplasia or absence of cerebellar vermis, the diagnosis is possible only in the second trimester, so beware not to falsely reassure or scare expecting parents. In conclusion, first trimester ultrasound could be useful for early detection of some CNS anomalies, but caution could be used for others, particularly in counseling couples about prognostic significant of ultrasound findings. How to cite this article Viora E, Polarolo G, Bastonero S, Gullino E, Stillavato S, Sciarrone A. Central Nervous System Anomalies Detectable in the First Trimester. Donald School J Ultrasound Obstet Gynecol 2017;11(4):261-267.

Sonographic detection of central nervous system defects in the first trimester of pregnancy.

The fetal central nervous system can already be examined in the first trimester of pregnancy. Acrania, alobar holoprosencephaly, cephaloceles, and spina bifida can confidently be diagnosed at that stage and should actively be looked for in every fetus undergoing first-trimester ultrasound. For some other conditions, such as vermian anomalies and agenesis of the corpus callosum, markers have been identified, but the diagnosis can only be confirmed in the second trimester of gestation. For these conditions, data on sensitivity and more importantly specificity and false positives are lacking, and one should therefore be aware not to falsely reassure or scare expecting parents based on first-trimester findings. This review summarizes the current knowledge of first-trimester neurosonography in the normal and abnormal fetus and gives an overview of which diseases can be diagnosed.

Holoprosencephaly: antenatal and postnatal diagnosis and outcome.

The objectives of this study are to ascertain the clinical outcome and overall survival of holoprosencephaly (HPE) patients diagnosed antenatally and postnatally, to determine the accuracy of antenatal diagnosis and to determine the role of neurosurgical intervention in HPE. This is a retrospective review over a 10-year period. Sixty-three patients were included in the study, 45 were diagnosed by antenatal radiological imaging and 18 were diagnosed by postnatal radiological imaging. Patient data was drawn from Temple Street Children's University Hospital (the national paediatric neurosurgery centre), the National Maternity Hospital in Holle's Street, Dublin, and Our Lady of Sick Children Hospital, Dublin. The study was carried out through a review of antenatal and postnatal radiological imaging and reports, clinical charts, GP letters from patient follow-up and telephone conversations with parents of HPE patients. Four patients in the antenatal diagnosis group had follow-up foetal MRI confirming HPE. Twelve in this group had radiological follow-up postnatally, and in five of these, HPE was confirmed. The remaining seven were identified as false positive. Alobar HPE constituted 55% (21/38) of patients with 95% mortality. Fifty-one percent had a normal karyotype. The overall survival in the antenatal diagnosis group was 13%. In the postnatal group, 18 patients were identified, 67% (12/18) lobar and 33% (6/18) semilobar. Normal karyotype was found in 72% (13/18), with an overall survival rate of 56% (10/18). Neurosurgical intervention in both groups mainly consisted of CSF diversion in the form of ventriculoperitoneal (VP) or cystoperitoneal shunt (CP) (13/67). Foetal MRI should be routinely performed in suspected cases of HPE, and reliance on ultrasound alone in the antenatal period may not be sufficient. In our study, there is a high early mortality noted in severe cases of HPE, while milder forms of HPE in children tend to survive beyond infancy albeit with associated complications that required neurosurgical intervention and medical management for other associated systemic anomalies.

Ethmocephaly: A rare cephalic disorder.

Dear Sir, A male neonate, product of nonconsanguineous marriage, was delivered vaginally with severe birth asphyxia (Apgar score 3, 4, 6) to a primiparous woman at 36 weeks’ gestation. The mother did not have any medical illness during pregnancy, and an antenatal ultrasound was performed at 29 weeks’ gestation which revealed holoprosencephaly with midline facial defect in the fetus. Examination after birth revealed weight of 2.6 kg, head circumference 31 cm (<3rd centile), facial dysmorphism (bilateral cleft lip, incomplete cleft palate, a central proboscis with a single nare, hypoplastic eyeballs, low-set ears), short neck with low hairline, widely spaced nipples, sandal gap in both feet, and bilateral simian crease [Figure 1]. He also had a large anterior fontanelle with widely separated sutures. The neonate received resuscitation at birth and was shifted to neonatal intensive care unit. He was put on mechanical ventilation and supportive therapy. Ultrasound of the head revealed undivided cerebral hemispheres with a single ventricle. Our neonate expired at 12 h of life following cardiorespiratory arrest. Karyotyping was performed which was reported as normal. Figure 1 Neonate with bilateral cleft lip, cleft palate, and a central proboscis with single nare and low set ears Ethmocephaly is the rarest phenotypic variant of a group of defects called the holoprosencephaly (HPE) malformation sequence;[1] other variants include cebocephaly, cyclopia, and median cleft palate. HPE is a cephalic disorder characterized by congenital brain malformation due to incomplete cleavage of the prosencephalon occurring between the 18th and 28th day of gestation. HPE is categorized into three levels of increasing severity: Lobar (where the right and left ventricles are separated, but with some continuity across the frontal cortex); semilobar (partial separation of hemispheres), and the most severe form alobar HPE (single brain ventricle and no interhemispheric fissure).[2] HPE can be caused by both genetic and environmental factors such as maternal insulin-dependent diabetes mellitus (1% risk of HPE),[3] maternal alcoholism, prenatal exposure to teratogens (alcohol, retinoic acid, cholesterol biosynthesis inhibitors, and maternal infections (cytomegalovirus, toxoplasmosis, rubella).[4] Some genetic associations with trisomy 13 or 18 have been reported.[5] Multiple malformation syndromes such as Kallmann syndrome, Pallister–Hall, Smith–Lemli–Opitz, and CHARGE syndrome have been found to be associated with HPE. However, nearly 70% cases are sporadic. Nearly all HPE malformation disorders have a fatal outcome during gestation or in early infancy. HPE can be detected by ultrasonography in the first trimester. Ultrasonographic markers include hypertelorism and a single common cerebral ventricle with absent midline echo. Other investigations include chromosomal analysis by karyotyping and genetic mutation analysis by denaturing high-performance liquid chromatography and multiplex polymerase chain reaction. Ethmocephaly is a rare cephalic disorder with a reported incidence of 1 in 15,000 among live births and 1 in 250 among abortuses.[1] It characterized by HPE with an undivided cerebrum and a single ventricle. In addition, there is a midline facial anomaly associated with a central proboscis, two well-formed orbits with absent or hypoplastic eyeballs, hypotelorism, and low set ears. It is differentiated from other HPE disorders namely cyclopia where the two eyes are fused together in a single median orbit and from cebocephaly which is characterized by a flattened nose with single nostril located below close-set eyes, based on the phenotype. Our case presented with midline facial defects, hypotelorism, bilateral microphthalmos, a central proboscis and bilateral low set ears, and alobar HPE, which are characteristic of ethmocephaly. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Analyse morphologique et tomodensitométrique comparée de deux nouveau-nés affectés d’une cyclotocéphalie

Two specimens of cyclotocephalic newborns, coming from museum collections, have been the subject of a comparative morphologic analysis. This one comprised an external examination and a CT scan exploration. If the craniofacial features were similar, one had a quasi-normal brain, while the second specimen displayed alobar holoprosencephaly. This observation relatively surprising is discussed in the light of current knowledge on the developmental genetics of this family of malformations.

Prenatal diagnosis of holoprosencephaly with proboscis and cyclopia caused by monosomy 18p resulting from unbalanced whole-arm translocation of 18;21

Abstract A case of holoprosencephaly (HPE) with proboscis, fused eyes in one orbit, and cyclopia was diagnosed by fetal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Ultrasonographic examination at 28 weeks of gestation showed fusion of the frontal part of the brain and ventricular dilation. Subsequent CT and MRI examinations confirmed this anomaly as alobar HPE. Amniocentesis followed by chromosome analysis demonstrated karyotype as de novo 45,XY, der (18;21)(q10;q10), with deletion of a short arm of chromosome 18. The pregnancy ended in a premature delivery of a male neonate weighing 1716 g at 34 weeks. Macroscopically, there were mid-frontal proboscis and single orbit with two eyes without normal nasal structures. He died 1 h after birth.

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18.

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon - closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support.

Lobar holoprosencephaly with Arnold-Chiari type III malformation

Holoprosencephaly (HPE) sequence is a rare spectrum of cerebral and facial malformations resulting from incomplete division of embryonic prosencephalon into diencephalon and telencephalon. De Meyer classified three ranges in order of in- creasing severity: lobar, semilobar and alobar HPE. A subtype called middle inter-hemispheric fissure variant has also been described. Arnold-Chiari III malformation is extremely rare and comprises of occipital encephalocele and associated cerebellar and brain stem abnormalities. This case report presents a male infant with lobar HPE and Arnold-Chiari III malformation without any facial defects and chromosomal abnormalities.

Distal 3p duplication and terminal 7q deletion associated with nuchal edema and cyclopia in a fetus and a review of the literature

ObjectiveTo present perinatal detection of distal 3p duplication and terminal 7q deletion associated with nuchal edema and cyclopia in a fetus, and to review the literature. Materials and methodsA 32-year-old, G9P0, woman who had experienced eight spontaneous abortions was found to have fetal nuchal edema, alobar holoprosencephaly, and cyclopia by prenatal ultrasound at 15 weeks of gestation. The pregnancy was subsequently terminated, and a malformed fetus was delivered with cyclopia. Molecular and conventional cytogenetic analyses were made to determine the genetic pathogenesis of fetal abnormalities. ResultsThe father had a karyotype of 46,XY,t(3;7)(p22.1;q36.1). The mother had a karyotype of 46,XX. The fetus had a karyotype of 46,XY,der(7)t(3;7)(p22.1;q36.1)pat. The analysis of array comparative genomic hybridization analysis revealed a 43.68-Mb duplication of 3p26.3-3p22.1 encompassing CHL1 and CNTN4, and an 8.66-Mb deletion of 7q36.1-7q36.3 encompassing SHH in the fetus. ConclusionSimultaneous occurrence of 7q deletion and 3p duplication can be associated with alobar holoprosencephaly. For the couple with a parental translocation involving 7q and 3p, prenatal ultrasound should include a detailed investigation of central nervous system anomalies.

Successful management of discordant alobar holoprosencephaly in monochorionic diamniotic twins with normal karyotype: a case report

Holoprosencephaly (HPE), a complex brain malformation resulting from incomplete cleavage of the prosencephalon into distinct cerebral hemispheres, is rare in newborns. Two preterm male neonates were born at 34 weeks’ and five days’ gestation in the monochorionic diamniotic twin pregnancy complicated with pre-eclampsia and intrahepatic cholestasis of pregnancy, and one of them was prenatally diagnosed with alobar HPE by ultrasonography with frontal bossing, hydrocephaly, hypotelorism of eyes, flat nasal bridge, macroglossia, and cheilo/palatoschisis at birth. Karyotyping by G-banding of amniocentesis specimens in normal twin and fetal umbilical blood in both fetuses showed 46, XY. This report expands discordant alobar holoprosencephaly in monochorionic diamniotic twins.

Alobar holoprosencephaly: A case report

Holoprosencephaly (HPE) is a rare congenital brain malformation associated with multiple midline facial defects. This anomaly is resulted from the failure of diverticulation and cleavage of primitive prosencephalon during weeks 4-8 of gestation. HPE is the most common forebrain developmental anomaly in human with the incidence rate of 0.49-1.2 cases per 10,000-20,000 term births. In this study, we described a case of HPE in a neonate with gestational age of 32 weeks. Antenatal ultrasonographic diagnosis was performed, and the infant was presented with macrocephaly, bilateral microphthalmia, hypotelorism, proboscis and ambiguous genitalia.

Hydranencephaly: cerebral spinal fluid instead of cerebral mantles

The authors report a wide and updated revision of hydranencephaly, including a literature review, and present the case of a patient affected by this condition, still alive at 36 months.Hydranencephaly is an isolated and with a severe prognosis abnormality, affecting the cerebral mantle. In this condition, the cerebral hemispheres are completely or almost completely absent and are replaced by a membranous sac filled with cerebrospinal fluid. Midbrain is usually not involved. Hydranencephaly is a relatively rare cerebral disorder. Differential diagnosis is mainly relevant when considering severe hydrocephalus, poroencephalic cyst and alobar holoprosencephaly. Ethical questions related to the correct criteria for the surgical treatment are also discussed.

Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects.

Sonic Hedgehog (SHH) and GLI2, an obligatory mediator of SHH signal transduction, are holoprosencephaly (HPE)-associated genes essential in pituitary formation. GLI2 variants have been found in patients with congenital hypopituitarism without complex midline cerebral defects (MCD). However, data on the occurrence of SHH mutations in these patients are limited. We screened for SHH and GLI2 mutations or copy number variations (CNV) in patients with congenital hypopituitarism without MCD or with variable degrees of MCD. Detailed data on clinical, laboratory and neuroimaging findings of 115 patients presenting with congenital hypopituitarism without MCD, septo-optic dysplasia or HPE were analysed. The SHH and GLI2 genes were directly sequenced, and the presence of gene CNV was analysed by multiplex ligation-dependent probe amplification (MLPA). Anterior pituitary deficiency was found in 74% and 53% of patients with SOD or HPE, respectively. Diabetes insipidus was common in patients with HPE (47%) but infrequent in patients with congenital hypopituitarism or SOD (7% and 8%, respectively). A single heterozygous nonsense SHH mutation (p.Tyr175Ter) was found in a patient presenting with hypopituitarism and alobar HPE. No other SHH mutations or CNV were found. Nine GLI2 variations (8 missense and 1 frameshift) including a homozygous and a compound heterozygous variation were found in patients with congenital hypopituitarism or SOD, but not in HPE patients. No GLI2 CNV were found. SHH mutations or copy number variations are not a common cause of congenital hypopituitarism in patients without complex midline cerebral defects. GLI2 variants are found in some patients with congenital hypopituitarism without complex midline cerebral defects or septo-optic dysplasia. However, functional analyses of these variants are needed to strengthen genotype-phenotype relationship.

Sirenomelia with associated systemic anomalies: An autopsy pathologic illustration of a series of four cases

Sirenomelia, a developmental defect involving the caudal region of the body, is associated with several internal visceral anomalies. We report a detailed spectrum of anomalies in an autopsy study of four fetuses with sirenomelia (gestational ages – 20, 21, 22.4, and 22.5 weeks). Three of the fetuses had single umbilical artery, with genitourinary and gastrointestinal anomalies. Central nervous system anomalies were evident in two of the fetuses, with alobar holoprosencephaly in one and lumbar meningomyelocele in another. The most common gastrointestinal anomaly was blind ended gut (imperforate anus), while esophageal atresia and omphalocele were noted in one case each. Renal hypoplasia was seen in two fetuses, renal agenesis in one and cystic renal dysplasia was noted in one case. Literature regarding pathogenesis of this condition is briefly discussed.