Hypothalamic hamartoma associated with multiple congenital abnormalities. Two patients and a review of reported cases

We report 2 patients with hypothalamic hamartoma associated with multiple congenital abnormalities and analyze 42 (including our own) reported cases, including our 2 cases, of hypothalamic hamartoma or hypothalamic hamartoblastoma with multiple congenital abnormalities, to understand the timing of their occurrence and clarify the prognosis. To this end, we classified them into lethal and nonlethal cases. We found poly- and syndactyly, cleft or high-arched palate and nose abnormalities to be important manifestations of this syndrome. Major organ abnormalities and CNS and endocrine abnormalities occurred frequently among the lethal cases, very likely indicative of a disturbance of embryogenesis between gestational days 34-37 and thus implicated in a negative prognosis.     

Fryns syndrome survivors and neurologic outcome

Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, unusual facies, and distal limb hypoplasia. It was first reported as a lethal condition. We report on a three-year-old survivor with Fryns syndrome, and provide a review on the outcome of other survivors. Patients who survive the neonatal period represent 14% of reported cases. Characteristics of survivors include less frequent diaphragmatic hernia and milder lung hypoplasia, absence of complex cardiac malformation, and neurologic impairment. Multiple central nervous system abnormalities have been reported in Fryns syndrome, including agenesis of the corpus callosum, Dandy-Walker abnormality, cerebellar heterotopias, cerebellar hypoplasia, enlarged ventricles, and hypoplasia of the olfactory bulbs. Our patient exhibited profound mental retardation. He had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm. Understanding of long-term outcome of survivors is important for counseling of families with Fryns syndrome. Careful brain examination is advised; however, a normal radiological brain examination does not preclude developmental delay. The spectrum of individual outcome and of associated anomalies indicates that individual evaluation, including imaging for structural brain malformation, is strongly advised.     

Congenital abnormalities associated with limb deficiency defects: a population study based on cases from the Hungarian Congenital Malformation Registry (1975-1984)

Limb deficiency defects (LD) occurring among 1,575,904 births in Hungary during 1975-1984 were reviewed. The overall birth prevalence of LD was 1 in 1,816. This paper discusses the nature and distribution of the limb and other defects in the 275 (32%) children who had structural malformations in other systems. Two main forms of classification were used: morphologic and causal. Additional malformations were most commonly seen in infants with amelia, rudimentary limb (RL), radial/tibial (RT), intercalary or central axis (CA) LD and rarely in those with terminal transverse (TT) or ulnar/fibular (UF) defects. Upper limbs (81%) were involved significantly more often than lower limbs (42%) and there were more right-sided defects (83% vs. 71%) due to an excess of right arm involvement especially with radial ray and split hand anomalies. Single limb involvement was relatively common with amelia (88%), UF (82%), RT (50%), and TT (50%) defects. With other LD, multimelic involvement was more characteristic. This was usually symmetric with intercalary and RL defects but asymmetric with CA anomalies and digital deficiencies (DD). From a causal perspective, 17% of cases had genetic disorders, 52% had recognized associations, anomalies, sequences, environmental causes or patterns of unknown origin, and 31% had unknown patterns of malformations. The commonest entities were amnion disruption sequence (16% of cases) and VACTERL association (8%). Both of these disorders showed unusual temporal distribution. As anticipated, patterns of malformations differed with the type of LD. Amelia and digital amputations were often seen with body wall defects, atypical anencephaly or encephalocele, and cleft lip reflecting amnion disruption. Rudimentary limb was seen with anencephaly, omphalocele, renal agenesis, aberrant genitalia, and imperforate anus, reflecting defects of blastogenesis including the cloacal exstrophy and caudal regression sequences and Schisis association. Radial/tibial defects were associated with different patterns depending on whether the limb defects were unilateral or bilateral. Unilateral defects occurred with anomalies suggesting VACTERL association or the facio-auriculo-vertebral anomaly, while bilateral defects occurred more often in genetic or potentially genetic disorders including VACTERL with hydrocephalus. Central axis defects showed three main patterns of association: one reflecting the ectrodactyly-ectodermal dysplasia-clefting syndrome; one with tongue anomalies representing a variant of oro-mandibular-limb (Hanhart) anomaly, and the last with hydronephrosis indicating a group of "acro-renal" syndromes. Strong associations with other anomalies were not seen in the groups with TT, UF, or intercalary defects.     

CHARGE syndrome: report of 47 cases and review

The acronym CHARGE refers to a syndrome of unknown cause. Here we report on 47 CHARGE patients evaluated for the frequency of major anomalies, namely coloboma (79%), heart malformation (85%), choanal atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness (62%). In addition, we comment on anomalies observed very frequently in neonates and infants with the CHARGE syndrome, including, minor facial anomalies, neonatal brain stem dysfunction with cranial nerve palsy, and, mostly, internal ear anomalies such as semicircular canal hypoplasia that were found in each patient that could be tested. We propose several criteria for poor survival including male gender, central nervous system and/or oesophageal malformations, and bilateral choanal atresia. No predictive factor regarding developmental prognosis could be identified in our series. A significantly higher mean paternal age at conception together with concordance in monozygotic twins and the existence of rare familial cases support the role of genetic factors such as de novo mutation of a dominant gene or subtle sub-microscopic chromosome rearrangement. Finally, the combination of malformations in CHARGE syndrome strongly supports the view that this multiple congenital anomalies/mental retardation syndrome is a polytopic developmental field defect involving the neural tube and the neural crests cells.     

MR of the normal neonatal brain: assessment of deep structures

BACKGROUND AND PURPOSE: Recent work has shown that up to 50% of patients with congenital muscular dystrophies (CMDs) have abnormalities of the brain that can be detected by brain MR imaging. We attempted to determine whether brain MR imaging is useful for the diagnosis and classification of patients with CMDs. METHODS: The brain MR studies of 12 patients with biopsy-proved CMDs were reviewed retrospectively. Using information available in the literature regarding associated brain anomalies as a guide, an attempt was made to classify the patients in terms of "pure" CMD, CMD with occipital agyria, Fukuyama CMD, muscle-eye-brain disease, or Walker-Warburg syndrome. RESULTS: All the patients were easily classified into one of four groups: pure CMD (four patients), Fukuyama CMD (four patients), muscle-eye-brain disease (two patients), or Walker-Warburg syndrome (two patients). Patients with pure CMD had diffuse central cerebral hypomyelination with mild pontine and cerebellar hypoplasia. Patients with Fukuyama CMD had diffuse central cerebral hypomyelination, cerebellar polymicrogyria (with or without cysts), frontal polymicrogyria, a variable degree of hypoplasia of the pons and cerebellar vermis, and a variable occipital cobblestone cortex. Patients with muscle-eye-brain disease had cerebellar polymicrogyria (with or without cysts), absence of the septum pellucidum, diffuse cerebral cortical dysplasia, pontine and cerebellar vermian hypoplasia, patchy hypomyelination, and variable callosal hypogenesis and hydrocephalus. Patients with Walker-Warburg syndrome had diffuse cerebral cobblestone cortex, absence of cerebral and cerebellar myelin, cerebellar polymicrogyria (with or without cysts), pontine and cerebellar vermal hypoplasia, hydrocephalus, and variable callosal hypogenesis. CONCLUSION: MR imaging shows distinctive brain anomalies that allows patients with CMD to be classified into four distinct groups that are consistent with known disorders.     

Congenital anomalies reflected in materials of obstetric ward of the Hospital of Internal Affairs in Warsaw during the period 1988-96

A congenital anomaly consists of a departure from the normal anatomic architecture of an organ or system. Malformations can be considered as the result of a developmental arrest of the primordium (incomplete morphogenesis), redundant morphogenesis, or aberrant morphogenesis. Congenital malformations establish more and more percentage of reason of incidence and morbidity in newborn and young children. It is also great family and social problem. The subjects studied were all cases of abnormality identified pre- or postnatally. The commonest system malformations were urogenitally tract, central nervous system, skeleton, craniofacial, heart and skin abnormalities. The most frequent single anomalies were--hypospadias, cleft lip/cleft palate, anomalies of hands and feet, vertebral malformations, meningocele, heart abnormalities and Down syndrome.     

The role of intraocular lenses in anterior chamber contamination during cataract surgery

The findings of prenatal ultrasound diagnosis were compared with the autopsy findings in 183 fetuses (between the 14th and 24th week of gestation), aborted for fetal malformations in the period from 1995 to 1997. In these 183 cases, the primary diagnosis showed 50 central nervous system anomalies, 48 cardiovascular system anomalies, 42 genitourinary system anomalies, 18 respiratory system anomalies, 8 skeleton system anomalies, 6 gastrointestinal system anomalies and 11 other abnormalities. Of the total number of cases, 41% had multiple malformations. In 144 cases (78%), the prenatal diagnosis was confirmed by autopsy, in 36 cases (20%) the prenatal diagnosis was confirmed with additional significant pathology, and in only 3 cases (2%) the prenatally detected malformation was not confirmed by pathological examination. Autopsy remains an important component of the evaluation of fetal losses after induced abortion.     

Autosomal chromosomes and anomalies of the oromaxillofacial area

The study deals with genetic diseases due to anomalies in the number and structure of autosomal chromosomes associated with oro-facial malformations. Pertinent literature from 1980 and clinical cases for each defect were analyzed. By comparing clinical signs and symptoms with chromosome abnormalities it was possible to build an analytical diagram showing the prevalence of malformation exhibited by each anatomical oro-facial region (cranial, labial, palatal, nasal, ocular, dental, lingual region). A very high prevalence of malformation was assessed for lip-and-palate regions (78%). These region often shows "micro-signs" of cleft lip and/or palate (deep palatal vault, maxillary hypoplasia, congenitally missing upper central incisors) which may indicate the presence of a mildly expressed chromosome abnormality. The whole sample of autosomal chromosome abnormalities induce anomalies in structures lying along body and face mid-line. The phenotypic expression of such anomalies may be defective (cleft lip and/or palate), or excessive as well (excessive thickness of the lingual frenum, broadening of the nasal bridge).     

TNF inhibits myogenesis and downregulates the expression of myogenic regulatory factors myoD and myogenin

Pulmonary agenesis is a rare malformation that can be isolated or associated with other anomalies. We became interested in pulmonary agenesis after evaluation of a child with right pulmonary agenesis, an unlobed left lung, bilateral cleft lip and palate, maxillary and mandibular hypoplasia, bilateral microtia, bilateral radial ray hypoplasia, horseshoe kidney, and complex congenital heart disease. A review of the occurrence of pulmonary agenesis with other congenital anomalies uncovered a striking association with ipsilateral radial ray defects and/or hemifacial microsomia. The presence of bilateral facial or radial ray anomalies was indicative of bilateral pulmonary involvement. A review of the cases of pulmonary agenesis and associated anomalies at the Children's Hospital and Medical Center confirmed the association of pulmonary agenesis and ipsilateral involvement of face and/or radial ray. The association of pulmonary agenesis and ipsilateral malformations may shed light on its pathogenesis. Although the cause of these associated anomalies remains unclear, abnormalities in the development of the aortic arches during embryogenesis is an attractive hypothesis.     

Solitary calcaneal cyst

A three-generation BO family is presented: the proband showed, in addition to branchio-oto malformations, a severe condition with growth retardation, mandibular hypoplasia and vertebral anomalies resembling the oculo-auriculo-vertebral (OAV) phenotype. This family study supports the hypothesis of Rollnick and Kaye that the OAV spectrum may represent, in some cases, an extreme component of the BOR syndrome. The finding has relevant implications for genetic counselling regarding both conditions.     

What constitutes an adequate smear in fine-needle aspiration cytology of the breast?

Du Pan syndrome is a rare condition comprising complex brachydactyly with fibular hypoplasia that is inherited in an autosomal recessive manner. This article describes experience gained through the management of four patients with this disorder. The surgical management of the upper limb abnormalities is discussed and a detailed timetable for their treatment is suggested.     

Fetal alcohol syndrome

The most notable features of fetal alcohol syndrome involve the face and eyes, and include microcephaly, short palpebral fissures, an underdeveloped philtrum and a thin upper lip. Evidence of intrauterine or postnatal growth retardation, mental retardation or other neurologic abnormalities, and at least two of the typical facial features are necessary to make the diagnosis. Newborns with the syndrome may be irritable, with hypotonia, severe tremors and withdrawal symptoms. Mild mental retardation, the most common and serious deficit, and a variety of other anomalies may accompany fetal alcohol syndrome. Sensory deficits include optic nerve hypoplasia, poor visual acuity, hearing loss, and receptive and expressive language delays. Atrial and ventricular septal defects, as well as renal hypoplasia, bladder diverticula and other genitourinary tract abnormalities, may occur. Complete abstinence during pregnancy is recommended, since alcohol consumption in each trimester has been associated with abnormalities, and the lowest innocuous dose of alcohol is not known.     

Radiation injury of the lung following postoperative radiotherapy of breast cancer using a single large portal technique--CT study

Magnetic resonance imaging demonstrated coexistent central nervous system abnormalities in 30 of 40 patients with optic nerve hypoplasia. Based on their associated neuroradiological findings, these patients were placed into one of five categories: group 1, isolated optic nerve hypoplasia; group 2, absence of the septum pellucidum; group 3, posterior pituitary ectopia; group 4, hemispheric migration anomalies; and group 5, intrauterine/perinatal hemispheric injury. Posterior pituitary ectopia (group 3) and cerebral hemispheric abnormalities (groups 4 and 5) were found to be highly predictive of pituitary hormone deficiency and neurodevelopmental deficits, respectively. Isolated absence of the septum pellucidum (group 2) was associated with normal neurodevelopmental and endocrinologic function. Thinning or agenesis of the corpus callosum was predictive of neurodevelopmental problems only by virtue of its frequent association with cerebral hemispheric abnormalities. Magnetic resonance imaging can now be used to provide specific prognostic information regarding the likelihood of neurodevelopmental deficits and pituitary hormone deficiency in infants with optic nerve hypoplasia. The prevailing notion of septo-optic dysplasia as a distinct nosologic entity should be reconsidered.     

Vater or Vacterl syndrome (author's transl)

Analysis of malformations in 65 newborns with limb anomalies, 39 with esophageal atresia with tracheoesophageal fistula, and 41 with anal atresia confirmed the nonrandom tendency for the defects of the VATER or VACTERL syndrome to associate together. 11 new patients with 4 or more of these anomalies were compared with 41 previously reported cases. There was good agreement with reference to the frequency of the major malformations noted in the VACTERL association. While anal atresia was not so common in our patients, cardiac anomalies and radial limb dysplasia occurred somewhat more frequently. In accordance with previous findings we also emphasize a single umbilical artery as one of the malformations in the spectrum of the VACTERL association (V = vertebral defects and vascular anomalies). Because of the high incidence of rib anomalies in our patients and in earlier cases with complete medical records it is suggested that the scope of the VACTERL association should be enlarged by this malformation. Thus the R in VACTERL would stand not only for renal defects but als for rib anomalies. Furthermore, the spectrum of anomalies could be extended by auricular defects (A = anal atresia and auricular defects). When one of these VACTERL components is found attention should be drawn to the possibility of the presence of the other associated anomalies. The developmentally correlated malformations seen in the VACTERL syndrome are generally sporadically observed. At the present time the etiology is unknown but heterogeneity is suggested. Although a causal relationship between maternal intake of progesteron/estrogen during the vulnerable period of embryogenesis and the VACTERL syndrome has been suggested, none of the mothers of our patients were exposed to these hormones during early pregnancy. Cytogenetic investigation in one patient and his mother showed a so-called marker chromosome 9 (C9qh+ variant) which is difficult to interpret at the present time.     

Incontinentia pigmenti: clinical and neuroradiologic features

Developmental brain malformations and destructive processes of unknown etiology were described in incontinentia pigmenti (IP). Two patients, a male and a female, with characteristic skin lesions and central nervous system (CNS) involvement are reported. Neuroradiological examinations revealed hypoplasia of corpus callosum, neuronal heterotopias, and periventricular white matter damage. No specific infectious, inflammatory, or metabolic abnormalities were identified. These neuroradiographic findings may suggest that an ischemic pathogenetic mechanism occurred prenatally. We speculate that the brain damage in IP may occur during CNS development and in successive stages. Magnetic resonance imaging appears more useful to detect white matter lesions and brain malformations in patients with IP.     

A modulatory effect of extracellular Ca2+ on type 1alpha metabotropic glutamate receptor-mediated signalling

DiGeorge syndrome or anomaly consists of a developmental field defect which is characterized by congenital absence or hypoplasia of the thymus and parathyroids, as well as facial dysmorphism and congenital heart defects. Other congenital malformations may coexist, in particular, thyroid abnormalities. A case of congenital hypothyroidism and DiGeorge syndrome is reviewed. Necropsy, clinical, and experimental studies also show that thyroid abnormalities may be a feature of DiGeorge syndrome. Although this could be purely coincidental, our case suggests that thyroid gland dysgenesis may be more common than previously thought. Thus, children with the DiGeorge syndrome may be at higher risk for hypothyroidism. Because of this potential association, patients who are considered to have this anomaly should have early newborn thyroid screening.     

Hypomelanosis of Ito

The main peculiarities of the hypomelanosis of Ito (HI) or incontinentia pigmenti achromians are shown. The most frequent and severe complications of this multisystemic neurocutaneous disease are reviewed. The most severe complications concern to the central nervous system (CNS), mental retardation and epilepsy--both present in more than 50% of cases--being the two most severe and frequent disorders. About 10% of patients with HI show infantile spasms during the first year of life and another 10% have autistic behavior. Moreover, other complications can be observed in some patients. These complications consist of ocular, musculoskeletal and oral alterations, hypotonia, macrocephalia, microcephalia, congenital cardiac malformations, urological and genital malformations and other rarer disorders. Chromosomal anomalies, especially translocations or mosaicisms type are found in about 50% of cases. The study, however, can show the chromosomal abnormalities in the karyotype performed in fibroblasts of the hypopigmented skin while it may be normal in the blood and in skin unaffected.     

The defective nature of hepatitis delta virus

Forty-nine out of 66 patients with Turner's syndrome and different karyotypes underwent full cardiological evaluations (physical examination, electrocardiography, chest X-ray and echocardiography). Congenital cardiovascular anomalies were found in 11 patients (22.4%). Among the cardiac anomalies in patients with Turner's syndrome, aortic malformations (aortic coarctation [27%], aortic stenosis [18%] and bicuspid aortic valve [18%]) were the most frequent. We observed that the most severe malformations were found in those with karyotype 45,X or 45,X/46,XX. No anomalies were detected in patients with the X isochromosome or those mosaic with the Y component.     

Inherited diseases of the glomerular basement membrane

The inherited diseases of the glomerular basement membrane include Alport's syndrome (AS), nail-patella syndrome, and thin basement membrane nephropathy. Classical AS is inherited in an X-linked manner and accounts for approximately 85% of the cases. Its manifestations include hematuria, sensorineural hearing loss, ocular defects, and a progression to renal failure. A defect(s) in the alpha 5 (IV) chain of type IV collagen is believed to be the etiology of classic AS, and alterations in its encoding gene localized to the X-chromosome have been elucidated. Although isolated cases of anti-glomerular basement membrane glomerulonephritis have been reported following renal transplantation in patients with AS, it is considered an effective form of renal replacement therapy. Less is known regarding the genetic basis of the autosomal-dominant form of AS, which apparently accounts for the remaining 15% of the cases. Nail-patella syndrome is characterized by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. It is inherited in an autosomal-dominant fashion with the gene locus assigned to the long arm of chromosome 9. Possible linkage between the COL5A1 gene and the gene for nail-patella syndrome has been suggested. Approximately 30% of the patients progress to end-stage renal failure. Renal transplantation has been successful in treating patients who progress to end-stage renal failure. Thin basement membrane nephropathy is an autosomal dominant trait that accounts for approximately 30% of the cases presenting as persistent, asymptomatic hematuria. The cause of thin basement membrane nephropathy is unknown at present. No decline in renal function is associated with thin basement membrane nephropathy.