GENESMED PROJECT:
1. NEUROLOGICAL DEFECTS IN 3,200 GENETIC DISEASES

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ISBN: 9788889142820

AUTHOR: VALERIO VENTRUTO

WEB DB ADMINISTRATOR: FELICE MARRONE

EDITOR: NATALINO MARRONE

THE NEXT E-BOOKS (The output order can be changed at the discretion of the publisher):

4,000 PRENATAL/NEONATAL GENETIC DISEASE INCLUDING LATE-ONSET DISEASES WITH MOLECULAR KNOWLEDGES

1,100 GENETIC DISEASES WITH REPRODUCTIVE SYSTEM DEFECTS

1,350 GENETIC DISEASES WITH GASTROENTEROLOGY DEFECTS

1,900 GENETIC DISEASES WITH EAR-NOSE-THROAT DEFECTS

2,000 GENETIC DISEASES WITH DERMATOLOGICAL DEFECTS

2,300 GENETIC DISEASES WITH CONGENITAL CARDIOVASCULAR DEFECTS

2,500 GENETIC DISEASES WITH OPHTHALMOLOGICAL DEFECTS

2,700 GENETIC DISEASES WITH ORODENTAL-CRANIOFACIAL DEFECTS

4,000 GENETIC DISEASES WITH SKELETAL-JOINT DEFECTS

900 GENETIC DISEASES WITH URONEPHROLOGICAL DEFECTS

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DNA: a means or an end?
Is the genotype a tool for the phenotype to make another phenotype
or is the phenotype a tool for the genotype to make another genotype?
A provocative question without an answer.

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It is worth noting that it is not a textbook of Neurological book but a book containing genetic diseases in which, in isolated forms or in syndromic associations, the anomalies of these structures may occur.
The aim is to offer an easy and up-to-date approach to the diagnostic recognition of the thousands of genetic diseases and congenital malformations. The purpose is to aid physicians who often encounter difficulty in the interpretation of the meaning and prognosis of signs, even if correctly observed.
The books making up the Encyclopedia are not textbooks of Specialized Medicine but for Medical specialists.
Even if gene analyses are frequently available they do not allow their prenatal molecular diagnosis, because knowledge of the genes involved does not always enable prenatal diagnostic application.

The word genetic is in everyday language. It does not apply to only specialized medicine. Medical students should know that every disease of the organs of the body occurs in hundreds of inherited syndromes. For instance, only few students know that hepatic chirrosis may be observed in 80 genetic diseases; when they study congenital cardiac defects, were not told they that prolapse of mitral valve occurs in 60 genetic syndromes; and the instances could go on. Nowaday particular attention deserves not only to the thousands of well-known inherited diseases, but also to the susceptibility towards the diseases. It is worth considering that the genome today tells you much more about predisposition to obesity, hypertension, diabetes, cardiac infart, tumors, etc. These knowledges are very useful for running special programme aimed at preventing these social diseases. From what till now said, the Authors suppose that it has been useful that any book of this series of publication has not restricted itself to a simply academic knowledges but also for not medical people useful data have been frequently integrated.

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COLLABORATORS

CANCEMI DINO
Ricerche e diagnosi genetiche Cancemi, Naples (Italy)

FRISO PATRIZIA
Azienda Ospedaliera A. Cardarelli, Naples (Italy)

LONARDO MARIA CONCETTA
Università degli Studi di Roma "La Sapienza"

LONARDO VALERIA
Università degli studi Federico II, Naples (Italy)

MORELLI FRANCO
Institute of Genetics and Biophysics. CNR Naples (Italy)

SPAMPANATO CARMINE
Telethon Institute of Genetics and Medicine (TIGEM) Naples (Italy)

URCIUOLI MARIA
Seconda Università degli Studi (SUN), Naples (Italy)

VENTRUTO MARIALUISA
Ospedale San Giuseppe Moscati, Avellino (Italy)

EMBRYOLOGIC DEVELOPMENT OF THE NEUROLOGICAL APPARATUS

Central Nervous System (CNS) development begins from the neural plate, a thickening in the ectoderm, at the end of the 2nd week.
Afterwards, two structures form in the neural plate, called the neural groove and the neural fold. The neural crest develops from the latter, on each side of which grow the somites. The neural fold starts its closure at the end of the 3rd week to form the neural tube. Going from the cranial to the caudal direction, three brain structures originate from the neural tube: the forebrain, midbrain and hindbrain. The term forebrain means prosencephalon, midbrain means mesencephalon and hindbrain means rhombencephalon.

The development of the forebrain

The forebrain (prosencephalon) develops in the telencephalon and diencephalon.

Telencephalon

From the telencephalon originate the cerebral cortex, nucleus caudate and corpus striatum of the basal ganglia, amygdaloid nucleus and claustrum.
The plexus choroids are formed by a layer of ependymal cells and the vascular mesenchime and protrude into the third ventricle. This structure develops during the 6th-7th week.
The corpus callosum is a commissure which connects the two cerebral hemispheres. It develops at about 10 weeks.
The olfactory bulbs (primary sensory neurons), together with the secondary sensory neurons, form the olphactory nerve. They are part of the oronasal structures and develop during the 2nd month.

Diencephalon

From the diencephalon there originates the thalamus, hypothalamus, globus pallidus and the eyes. It also gives rise to the epiphysis (pineal body) and hypophysis (pituitary gland). This gland is composed of two parts, named respectively the infundibulum and Rachke’s pouch. From the former the posterior lobe of the gland (pars nervosa) develops, while from the latter the anterior lobe (adenohypophysis) originates.
Its normal place is at the 6th week of development and its maturation occurs at different rates. At about 12 weeks a midline portion, called the vermis, may be observed, which is between the two lateral portions, called the cerebellar hemispheres.
A portion of the metencephalon forms the pons, containing several motor and sensory nuclei, such as V, VI and VII.

Myelencephalon

From the myelencephalon originates the medulla oblongata, a structure containing several important motor nuclei, such as the hypoglossal nerve, the nerves of the ocular muscles (abducens, trochlear and oculomotor), the nerves of the pharyngeal arch muscles (vagus, glossopharyngeal and accessory nerves) and the nerves of the involuntary muscles of the heart, lung and gut.
Together with the motor nuclei, the region also contains sensory nuclei, including the trigeminal and vestibulococlear nerves.

Ventricles

The cavity of the rhombencephalon forms the fourth ventricle.
From the cavity of the diencephalon the third ventricle originates.
The lateral ventricles originate from the cavity of the cerebral hemispheres, which grow from some pouchings of the telencephalon.
The Aqueduct of Sylvius is a narrow mesencephalic lumen which connects the third and fourth ventricle. Its stenosis induces a particular hydrocephaly.
The left and right foramina of Moro connect the third ventricle with the two lateral ventricles respectively.
The growth of the ventricles occurs mainly by internal pressure.

The development of the skull

The cranial ossification has two origins: intramembranous and enchondral. The former gives rise to the cranial vault while the latter gives rise to the cranial basal, consisting in the occipital bone, sphenoid, ethmoid, petrous and the mastoid portions of the temporal bone. Sutures and fontanels are observed in the cranial vault for some time into childhood. These structures consist in dense connective tissue membranes and separate the bones of the vault.

The development of the paranasal sinuses (sphenoid, frontals, ethmoids and maxillary sinuses)

Sinuses are visible during the third foetal stage of development. Besides in the sinuses, pneumatization also occurs in the mastoid antrum and temporal bones. Normally only some of these structures are visible by radiological examination at birth.

The development of the spinal cord

The spinal cord consists of a pseudostratified epithelium growing in the closed neural tube. The two layers of the spinal cord, named respectively the mantle layer and marginal layer, will have different destinations.
The cells of the former form the neuroepithelium from which the primitive nerve cells, named neuroblasts, originate.
From the neuroblasts the gray matter will originate.
The destination of the cells of the marginal layer is to form the white matter.
From the spinal cord originate also two different areas, named respectively the motor area and the sensory area. The former contains the motor horn cells, while the latter, dorsally placed, contains the sensory horn cells.
The neuroblasts show a primitive round and apolar form. Later they assume a bipolar form, due to the development of two processes on the opposite sides of these cells. Successively they become multipolar, because of the elongation respectively of the axon and the dendrites.
These multipolar cells will be the adult nerve cells, named the neurons.
From the neuroepithelium the glial cells also originate, from which other differentiated cells, called astrocytes and oligodendroglia, develop.
The Schwann cells originate from the neural crest and myelinate the peripheral nerves.

Metabolic disorders occur in about 2,000 genetic diseases. Mental retardation may be observed in about 1:4.

The IV Section includes 1,200 genetic diseases with neuropsychic disorders. Mental retardation occurs in many of these defects.
For instance, speech disorders and defects may be observed in 150 genetic diseases and mental retardation in most of them.

The genetic characteristics of the neurological tumors are in the V Section of the Book. It is woth considering their frequency and the juvenile occurrence.

PREFACE

Estimate of frequency of genetic disorders

Even if clinical genetics has now entered every field of Medicine, many doctors still believe that there are no more than about fifty genetic diseases in their own fields. They sometimes have just a vague memory of them from the time when they were enrolled at university and they are convinced that during their professional careers they have only encountered them a few times, if at all. In fact it is a widespread opinion that genetic diseases are very rare. This is true when they are taken individually; as a whole, however, their frequency is remarkable in that they are a significant cause of morbility and mortality. This can be understood even more clearly if we look at the dramatic decrease of environmental causes, at least in developed countries. According to some estimates, chromosomal abnormalities are present in about 6 in 1,000 liveborn infants and the same incidence holds also for autosomal dominant disorders; autosomal recessive diseases occur in 3 of 1,000 and X-linked in more than 1 in 1,000 liveborn infants, so that – not counting diseases with multifactorial inheritance – Mendelian inherited disorders occur in more than 1% of the population.
The number of births in many countries has recently dimished, not on account of economic factors but for cultural and social reasons. Consequently there has been an increased demand from families to the medical profession to have “perfect children”. They are aware of the possibilities in many cases of prenatal diagnosis: in fact scientific progress has created a new field of prenatal medicine, related to the observation of anomalous intrauterine development and embryo-fetal pathologies. In several inherited diseases there is at present the opportunity for prenatal recognition by ultrasound techniques, gene analyses, chromosomal studies and many other laboratory analyses. Many causes of fetal disorders are now known: from chromosomal abnormalities to gene mutations, from congenital malformations to fetal defects due to maternal infections, etc.
Purely genetic factors account for many congenital anomalies. Many statistical studies show that children with genetic diseases or congenital malformations account for 30% of admissions to paediatric hospitals. Suffice to say that there are more than 5,000 Mendelian genetic diseases: if any of them has a frequency of 1 in 100,000 live births, at least 5% of people will have the possibility of being born with a genetic anomaly, either a malformation or a functional deficit that may not become apparent until later in life.
About 20% of infant mortality is due to genetic diseases and congenital malformations.
These figures are an underestimation of reality because many hereditary disorders have a frequency greater than 1 in 100,000 live births. For instance: Retinoblastoma (1 in 20,000), Cystic fibrosis (1 in 4,000), Duchenne muscular dystrophy (1 in 7,250), Steinert myotonic dystrophy (1 in 8,000) Thalassemia major (1 in 10,000), Phenylketonuria (1 in 10,000), 21-hydroxylasis deficiency (1 in 10,000), Monogenic hypercholesterolemia (1 in 500), CHARGE association (1 in 12,000), Neurofibromatosis (1 in 2,000), etc.
Many genetic diseases are not diagnosed at birth because the clinical signs do not manifest themselves until later in life (this is especially true for several hereditary diseases of the eye and neuromuscular apparatus).
The frequency of these pathologies is even greater if, in addition to post-partum births, we also take into consideration pre-partum beings with lethal genes. In fact high prevalence of miscarriages is due to chromosomal abnormalities and genetic mutations. The prevalence of miscarriages has been considered to be about 15% between weeks 5 and 28 of any gestation. The mechanisms of miscarriages are not well understood. It is worth considering that about 50% of miscarriages occurring in the embryonic period are due to chromosomopathies.
Unfortunately only a few families at risk are aware of these facts.
Major congenital anomalies, that is anomalies which induce significant pathologies, are present in about 2% of newborn children, and the so called minor congenital anomalies are present in more than 10% of newborn children. The causes of the malformations may be due to either genetically determined intrinsic or extrinsic factors (for example, the teratogenic effect of some drugs). It is worth emphasizing that minor defects are sometimes the only visible signs of more important disorders that are not yet evident at birth; for instance, the polydactyly in Bardet-Biedl syndrome, where mental retardation, retinopathy and other defects occur later in life.
Tumors may develop in the intrauterine period and be present at birth or may be detected later in paediatric age. They consist mainly in teratomas and hamartomas.
Neural tube defects (NTD) are very common congenital disorders. They may be observed in a range of forms from severe and lethal forms such as anencephaly to asymptomatic spina bifida occulta. Most of NTD have multifactorial inheritance, but there are more than 100 with Mendelian inheritance.
Orodentocraniofacial anomalies are very frequent in genetic disorders, occurring in about 2,800 diseases. There are over 200 genetic disorders inducing lip and palate cleft, more than 500 diseases with microcephaly (not always congenital) and over 250 syndromes with hydrocephalus.
Today, in the field of ocular diseases, we are able to observe many defects with ultrasound instruments, including even congenital cataracts that occur, as isolated genetic defects or in syndromic associations, in over 300 diseases.
Malformations of the cardiovascular system occur in about 1% of children. They may be discovered in utero by echocardiography and are present in over 15% of miscarriages and stillborn fetuses. Despite the high incidence, it is supposed that cardiopathy is only rarely the cause of intrauterine death. Congenital cardiopathies have been reported in about 600 genetic disorders.
Lung development anomalies are not frequent; trachaeal agenesis and tracheoesophageal fistulas with or without esophageal atresia occur in more than 20 genetic disorders.
There are about 40 sex reversal disorders that may be the cause of conflictuality between the cytogenetic results and the echographic data. Usually the controversial point consists in the fetus resulting phenotypically female and genotypically male. There are about 100 syndromes with ambiguity of reproductive system, one third of them may benefit from gene analysis (see Book Prenatal-neonatal genetic diseases).
It is an opinion of the Authors that after reading these data doctors will be convinced that the genetic syndromes of his own area of interest do not number about fifty, as previously believed, but rather several hundred.
It is worth considering that this is not a book of Specialized Medicine but for Specialized Physicians.
The aim is to offer an easy and up-to-date approach to the diagnostic recognition of the thousands of genetic diseases and congenital malformations. The purpose is to aid physicians who often encounter difficulty in the interpretation of the meaning and prognosis of signs, even if correctly observed.

Contents of the book

As the syndromes usually involve more than a single apparatus most of them are posted in more than one book. For instance: the osteochondrodystrophies associated with deafness, choroidoretinal defects and epilepsy are reported in four books. In the same way, a syndrome having deafness, cleft lip and mental retardation is reported in the books of genetic syndromes of Auditory, Orodentocraniofacial and Neuromuscular apparatus.

For each disease the following features are reported:

Name of the disease

Eponyms and acronyms

Modes of transmission, inheritance

Groups, sub-groups and signs

Aggregations

Supergroups

Semiological synthesis

Differential diagnosis

bibliography

Images (in some diseases)

Examples

1-2 Name of the disease, eponyms and acronyms

There are more than 7,250 diseases and about 10,000 eponyms and acronyms
Example:

Achondrogenesis II has the following eponyms and acronyms;

ACG2, Achondrogenesis type IB, Langer-Saldino type of Achondrogenesis, Hypochondrogenesis.

3. Modes of transmission, inheritance

There are more than 15 types of inheritance.

autosomal dominant

autosomal recessive

X-linked recessive

genetic heterogeneity

autosomal recessive with pseudodominance

contiguous genes duplication

early somatic mutation/gametic half-chromatid mutation

chromosomic

supposed X-linked dominant

mitochondrial

no genetic

sex-limited, sex influenced

……..

4. Groups-subgroups-signs

The groups refer to the apparatus involved in the disease:

Auditory diseases

Cardiovascular diseases

Dermatological diseases

Endocrino/metabolic diseases

Reproductive system diseases

Gastrointestinal diseases

Haemopoietic-lymphoreticular diseases

Uronephrological:

Joint diseases

Neoplastic diseases

Muscular diseases

Laboratory modified data

Ocular diseases

Neurological diseases

Orodentocraniofacial diseases

Prenatal-neonatal diseases

Respiratory diseases

Skeletal diseases

Uronephrological diseases

The subgroups refer to the components of each group. There are about 200 subgroups.
Examples:

Eyelids changes, Iris anomalies,Visus defects, Lacrimal gland-lacrimal sac defects are some of the subgroups of the group Ocular disease.

Tongue changes, Outer ear anomalies, Teeth modified structures, Forehead changes, Palatopharyngeal changes, Mandibular changes are some of the subgroups of the group Orodentocraniofacial diseases.

The signs refer to the characteristics of each subgroup. There are more than 10,600 signs, about 4,000 of them are gene mutations.
Examples:

Blepharophimosis, Ectropion, Distichiasis, Palpebral ptosis are signs of the subgroup Eyelids changes of the group Ocular diseases.

Cerebellum vermis hypoplasia, Fetal banana sign, Cerebellar hypoplasia are signs of of the subgroups Cerebellar changes of the group Neurological diseases.

Hypoplastic radius and radial absence are two of signs of the subgroup radioulnar changes belonging to the group skeletal disorders.

Agnathia-severe micrognatia belongs to the subgroup mandibular changes of the group orodentocraniofacial anomalies. Fetal fractures and hydrops are 2 signs of the subgroup fetal changes of the group Prenatal-neonatal data.

5. Aggregations

There are mor than 200 aggregations that represent some utilities either for a nosographic collocation of the diseases or to facilitate differential diagnosis.
Aggregations include diseases linked by specific, common clinical and/or metabolic features.
Some examples are:

Acrofacial dysostosis;

Ehlers Danlos diseases;

Epidermolysis bullosae;

Metabolic alkalosis;

Isolated urinary tract defects

Mesomelic dwarfisms;

Complement defects;

Immunological disorders;

Fetal changes induced by environmental agents;

Cationic aminoacidurias;

Distrectual arthrogryposis;

Mitochondrial fatty acid oxidation disorders

6.The Supergroups

The supergroups have been created in order to facilitate the clinical pathways.
There are more than 50 of thesesSupergroups: facio-neuro-ocular; skeleto-ocular; neuro-acoustic; facio-oto-renal; orofacio-gastrointestinal; dysmorphic face-mental retardation-deafnes, etc.
Examples:

Heart-hand syndrome, also known as Holt-Oram syndrome, is included in the supergroup Cardio-skeletal disorders;

Usher diseases are included in the supergroup Acustic-oculo disorders;

Lorenz type of acrocephalosyndactyly, Apert syndrome and Cerebro-costo-mandibular syndrome are included in the supergroup Facio-neuro-skeletal disorder.

7. Semiological synthesis

The semiological synthesis of each disease is preceded by the name of a supergroup, which is the indication of the main structures involved in that disorder.
Examples:

The semiological synthesis of KID syndrome is preceded by the supergoup auditory-cutaneous disorder;

The semiological synthesis of Larsen syndrome is preceded by the supergroup arthro-auditory-facio-skeletal.

8. differential diagnosis

It is important to differentiate syndromes which may be apparently alike among each others because they may have different mode of inheritance and not the same molecular defects.
Examples:

Thanatophoric dysplasia II must be differentiate from Cloverleaf skull syndrome, Knowles-Winter syndrome and Thanatophoric dysplasia I.

CHARGE association (also known as Hall-Hittner syndrome) must be differentiate from more than 10 genetic syndromes.

9. Bibliography

The bibliography of each genetic diseases contains references of OMIM and of the magazines containing data concerning the syndrome or some of its characteristics.

10. Images

Link to images on internet

11. This book contains 5 sections and 29 chapters:

BRAIN DEFECTS

NEURAL TUBE DEFECT. SPINAL CORD, CHANGES. PERIFERAL NEUROPATHIES

NEUROLOGICAL DISEASES WITH ENDOCRINAL-METABOLIC DEFECTS

COGNITIVE-BEHAVIORAL AND OBSESSIVE/COMPULSIVE DISORDERS IN GENETIC DISEASES

NEUROLOGICAL TUMORS

It is worth considering that mental retardation occurs in 50% of genetic diseases with neurological defects.

SECTION V.
NEUROLOGICAL TUMORS

CHAPTER 29
GENETIC DISEASES WITH NEUROLOGICAL TUMORS

29.1 NEUROLOGICAL TUMORS IN GENETIC DISEASES

There are about 30 types of neurological tumors, some of these have infancy/juvenile onset. Gene analyses are available in most of them.

29.2 GLIOMAS/PARAGLIOMAS

Gliomas are parenchimal neuroectodermal tumors that start in the brain or spine, araising from glial cells, involving the macroglia. The most common site of gliomas is the brain.
There are 15 genetic diseases in which these tumour occour.

DISORDER | APP-Code
Carotid body tumor | 4405
Ganglioglioma | 1653
Glioma of the brain 1-8 | 10740
Gliomatosis peritonei | 1745
Nasal glioma | 18520
Norrie disease | 18460
Oligodendroglioma | 351
Optic nerve glioma | 19220
Osteoporosis-pseudoglioma syndrome | 19730

Ganglioglioma also named Desmoplastic infantile ganglioglioma or Papillary glioneuronal tumors, is sporadic tumor. The gene mutation is on chromosome 19p13.3. Characteristic defects: a new entity of glioma defined morphologically as glioneuronal tumors of the central nervous system, composed of mixed populations of glial and neuroepithelial elements, occurring mostly in infancy, with common sites in temporal lobes. Chromosome deletions have been observed.

Glioma of the brain 1-8 also named Astrocytoma or Glioblastoma, multiforme, has genetic heterogeneity. The gene mutations are on chromosomes 19q13.3, 10q25.3-q26.1, 7p12.3-p12.1, 1p36.1-p35 and others. Characteristic defects: infancy/childhood onset; seizures, progressive weakness, speech/visual disturbances, multifocal glioblastoma involving frontal-temporal lobes, other areas. GBM arises from astrocytic cells. Primary brain cancer has been observed in families with a high risk of prostate cancer.

Gliomatosis peritonei is sporadic disease. The gene mutation is unknown. Characteristic defects: nodules of mature glial tissues in the peritoneum associated with ovarian immature teratoma.

Nasal glioma is sporadic disease. The gene mutation is unknown. Characteristic defects: congenital extranasal/intranasal nasopharyngeal neurogenic benign tumors, producing broad nasal bridge, widely set eyes, occasionally connected with subarachnoid space.

Norrie disease, also known as Atrophia bulborum hereditaria, has X-linked recessive inheritance. The gene mutation is on chromosome Xp11.4. This syndrome is characterizeed by bilateral leukocoria at birth, microphthalmos, other ocular defects; intraocular retrolental masses, bilateral occasionally retinal changes resembling pseudoglioma. Mental retardation, late-onset deafness, hypogonadism.

Oligodendroglioma is a rare, slow-growing brain tumor arises from cells called oligodendrocytes. It has genetic heterogeneity. The gene mutation are on chromosomes 10,19. Characteristic defects: adulthood onset. Tumor composed of neoplastic oligodendrocytes located in the cerebral white or deep gray matter. Less malignant transformation than astrocytomas.

Optic nerve glioma also named Orbital nerve, glioma, is sporadic disease. The gene mutation is unknown. Characteristic defects: proptosis, visual loss, optic atrophy, juvenile type pilocytic astrocytoma.

Osteoporosis-pseudoglioma, also known as Blindness pseudogliomatous-osteoporosis-mild mental retardation, has autosomal recessive inheritance and has been cinsidered as the ocular form of osteogenesis imperfecta. The gene mutation is on chromosome 11q13.4. The features of this severe disease are short trunk, fractures, blindness, retinal detachment, pseudoglioma, cataract, corneal fractures, osteoporosis, deformities and joint laxity.

Carotid body tumor also named Chemodectoma of neck or Glomus jugulare tumors, has autosomal dominant inheritance. The gene mutation is unknown. Characteristic defects: painless, neck mass flushing by arteriography in the carotid bifurcation region, dysphagia, cough, syncope, cranial nerves paralysis, dysphagia.

29.3 PARAGANGLIOMA, NONCHROMAFFIN NEUROENDOCRINE NEOPLASM, GLOMUS JUGULAR TUMORS

This neurological defect occurs in 6 genetic diseases. Gene analysis are available in 5, no mental retardation

DISORDER | APP-Code
Carney triad | 9839
Carotid body tumors-multiple extradrenal pheochromocytomas | 4406
Gastrointestinal stromal tumors | 1175
Lee-Nicholson-Hitchcock syndrome | 14510
Multiple glomus tumors | 10750
Paraganglioma 1-3,5 | 20030

Paraganglioma also named Chemodectoma of middle ear or Glomus tympanicum tumors, has autosomal dominant inheritance with genetic heterogeneity, anticipated onset. The gene mutations are on chromosomes 11q23, 1q21, 5p15.33. Characteristic defects: nonchromaffin paraganglioma; middle ear mass, inducing hearing loss, tinnitus, bleeding, vertigo, cranial nerve palsies, other disturbances. Maternal imprinting (inactivation of the PGL gene). Possibility of anticipated onset.

Gastrointestinal stromal tumors also named Paraganglioma-gastric stromal sarcoma, has autosomal dominant inheritance with genetic heterogeneity. The gene mutations are on chromosomes 10q22-q24, 1q32, 1p36.1-p35. Characteristic defects: adulthood onset. Rare mesenchymal tumors of the gastrointestinal tract, derived from a precursor of interstitial cells of Cajal. Most of these tumors develop in the stomach. Occasionally they occur in the small intestine, and less frequently in the oesophagus, colon and rectum, intestinal obstruction, constipation.

Carney triad also named astric leiomyosarcoma-pulmonary chondroma-extraadrenal paraganglioma is sporadic disease sex-limited, sex influenced. The gene mutation is unknown. Characteristic defects: gastric leiomyosarcoma, pulmonary chondroma, extraadrenal paraganglioma.

Carotid body tumors-multiple extradrenal pheochromocytomas also named Paragangliomas 4, has autosomal dominant inheritance. The gene mutation is on chromosome 1p36.1-p35. Characteristic defects: adulthood onset. Signs of chemodectomas associated with extra-adrenal pheochromocytomas, headache, hyperhydrosis, dysphagia, tachycardia, other disorders. Gastric cancer tendency.

Pseudoglioma of retina also named Retinal nonattachment, nonsyndromic congenital, has autosomal recessive inheritance. The gene mutation is on chromosome 10q21. Characteristic defects: retinal changes inducing a large retrolental mass resembling glioma, retinoblastoma.

29.4 NEUROBLASTOMA

Nauroblastoma is an embryonal tumor that evolves from the neural crest cells. It may arise at any site in the sympathetic nervous system, inducing calcifications, hypertension, fever, sweating, abdominal pain, anorexia, diarrhoea, other cutaneous-neurovisceral findings. Horner's signs. It has characteristic laboratory data.
The majority of cases are sporadic. Risk for subsequent affected children: 1%; subsequent risk; if two sibs are affected: 30%. Congenital or neonatal occurrence of the tumor is relatively rare.
Paratesticular neuroblastoma is sporadic congenital tumor which must be differentiated from a testicular torsion. Nauroblastomas may occur also in Weaver syndrome and he rare Michelin-tire baby syndrome.

DISORDER | APP-Code
Ewing sarcoma | 23200
Michelin-tire baby syndrome | 16480
Neuroblastoma 1-6 | 18110
Paratesticular neuroblastoma | 1259
Weaver syndrome 1,2 | 26660

Weaver syndrome also named Moreno-Zachai-Kaufman syndrome, has autosomal dominant inheritance with genetic heterogeneity. The gene mutations are on chromosomes 7q36.1, 5q35. Characteristic defects: macrosomia, macrocephaly, deceleration of growth in childhood, accelerated skeletal maturation, camptodactyly, spasticity, dysmorphic face, hernia, mental retardation, bulimia, other defects. Neuroblastoma, ovarian tumors, sacrococcygeal teratoma have been reported in Weaver syndrome.

Neuroblastoma 1-6 has autosomal dominant inheritance with genetic heterogeneity, sporadic. The gene mutations are on chromosomes 2p23.2-p23.1, 6q22.33, 6p22, 2q35, 1q21.1 and others. Characteristic defects: embryonal tumor that evolves from the neural crest cells. It may arise at any site in the sympathetic nervous system, including the brain, the cervical region, the posterior mediastinum, the para-aortic sympathetic ganglia, the pelvis, mainly the adrenal medulla. Calcifications, hypertension, fever, sweating, abdominal pain, anorexia, diarrhoea, Horner's signs, other cutaneous-neurovisceral findings, characteristic laboratory data. The majority of cases are sporadic. Risk for subsequent affected children: 1%; subsequent risk, if two sibs are affected,: 30%. Congenital or neonatal occurrence of the tumor is relatively rare.

Michelin-tire baby syndrome has autosomal dominant inheritance. The gene mutation is on chromosome 1p13.2. Characteristic defects: limb/trunk symmetric pronounced folding of skin, resembling a Michelin-tyre, without amputation/strangulation/limb deformities, localized neuroblastoma, other minor anomalies. May occur a spontaneous resolution of skin creases in childhood.

Paratesticular neuroblastoma is sporadic disease. The gene mutation is unknown. Characteristic defects: this congenital tumor must be differentiated from a testicular torsion.

Ewing sarcoma is sporadic disease. The gene mutation is on chromosome 22q12.2. Characteristic defects: childhood/adulthood onset; painful swelling, usually bone extremity destruction, with a soft tissue mass; high frequency of metastasis, characteristic chromosome rearrangement.

29.5 NEURINOMA/SCHWANNOMA

This neurological defect occurs in 5 genetic diseases. Gene analysis are available in 3, mental retardation in Noonan syndrome.

DISORDER | APP-Code
Carney syndrome-1,2 | 4380
Gibberd-Gavrilescu syndrome | 9955
Globular neuropathy | 9956
Noonan syndrome 1 | 18430
Schwannomatosis 1-2 | 18151

29.5.1 DNA ANALYSIS

DISORDER | APP-Code
Carney syndrome-1,2 | 4380
Noonan syndrome 1 | 18430
Schwannomatosis 1-2 | 18151

Schwannomatosis, also called Acoustic neurinoma, bilateral, has autosomal dominant inheritance with genetic heterogeneity. Genomic imprinting due to uniparental disomy may occur. The gene mutation is on chromosome 22q12.2. The main characteristics are: bilateral acoustic neuromas, spinal/paraspinal signs, few cafè-au-lait spots or neurofibromas, retinal hamartoma, no Lisch nodules. Optic nerve glioma or pseudoglioma, retinal nodules, other defects. Potentially maternal imprinting. Prevalence: 1 in 30,000 live births.

29.6 PHEOCHROMOCYTOMA

This neurological defect occurs in 6 genetic diseases. Gene analysis are available in most of them, no mental retardation.

DISORDER | APP-Code
Carotid body tumors-multiple extradrenal pheochromocytomas | 4406
MEN 2A syndrome | 16180
MEN syndrome 3(2B),4 | 16190
Neurofibromatosis 1 | 18150
Neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome | 18154
Paragangliomas 4 | 20800
Pheochromocytoma-islet cell tumor | 20805
Von Hippel-Lindau syndrome | 26520

29.7 GENETIC DISEASES WITH NEUROLOGICAL TUMOR SUSCEPTIBILITY

There are 9 genetic diseases with these characteristics. Gene analysis are available in all of them.

DISORDER | APP-Code
Cowden disease 1-6 | 11600
Giant cell-fibroblastoma disease | 7235
Hunter- MacDonald syndrome | 6186
Neurofibromatosis 1 | 18150
Papilloma of coroid plexus | 5561
Radiation-induced meningioma | 9811
Rhabdoid tumor 1,2 | 28692
Tuberous sclerosis 1,2 | 23560
Werner syndrome | 26720