Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases
Developmental Anomalies and Defects

Significant genetic defects of a genomic nature severely disrupt embryonic development and are most frequently lethal. An increase in the chromosome number that is a multiple of the haploid set (various types of polyploidy) is predominantly found in Spontaneous Abortion material. The scientific literature describes isolated cases of live births who died shortly after, or stillbirths, with triploidy, meaning a chromosome count of 69 instead of 46. During the Cytology/cytology/16.html">Early stages of embryonic development, abnormalities in the number of individual Chromosomes—such as monosomy and trisomy—are also lethal.

Children with an altered number of sex chromosomes can successfully complete embryonic development and be born alive (in cases of genomic-level damage); these include Turner syndrome (45, X0); X polysomy (47, XXX; 48, XXXX, etc.); Klinefelter syndrome (47, XXY; 48, XXYY; 48, XXXY, etc.); and the trisomic variant of Down syndrome (47, XX (XY) +21).

Turner syndrome and Down syndrome manifest in early childhood with a characteristic set of Multiple developmental malformations. Klinefelter syndrome is most frequently diagnosed during Puberty, whereas X polysomy is usually detected incidentally and does not always affect the female phenotype. For a long time, changes in chromosome number were considered a *de novo* process—the consequence of accidental meiotic nondisjunction in one of the parents. Such cases were used to monitor mutation rates. However, data exist confirming the heritability of factors that cause meiotic chromosome nondisjunction. A potential role is attributed to Transposons (including viral DNAs integrated into the human Cell genotype) as agents that provoke non-homologous conjugation, leading to aneuploidy (an abnormal chromosome count not multiple of the haploid set) in the fetus. Among regular trisomies manifesting from birth, mention should be made of Edwards syndrome (47, XX (XY) +18), Patau syndrome (47, XX (XY) +13), and trisomy 8 (47, XX (XY) +8).

Chromosomal diseases caused by structural Chromosomal aberrations encompass Numerous Congenital Malformations, as this pathology is likewise associated with major defects and rearrangements of the genetic apparatus. The refinement of cytogenetic diagnostic techniques has made it possible to reclassify certain malformations from syndromes of unknown Etiology into this group of disorders. Currently, syndromes of complete trisomy for groups G, E, and D, as well as partial trisomy and partial monosomy for all Human chromosomes, have been described. These are characterized by anomalies in The Development of the Skull, limbs, eyes, ears, Hard and Soft palates, frequently a cleft lip, intellectual and physical disability, prematurity, and intrauterine growth restriction at birth. A combination of these anomalies is typical of various syndromes. This pathology, present in a child from the very first moments of life—and detectable in the fetus via prenatal Diagnosis—serves as an indication for cytogenetic examination. Among chromosomal aberrations, the best known are cri-du-chat syndrome (46, 5p-) and Wolf-Hirschhorn syndrome (46, 4p-). According to recent data, cat-eye syndrome (46, +22q or 47, +der 22) and Prader-Willi syndrome (46, 15q-) are also Chromosomal Disorders in whose etiology Genomic Imprinting plays a significant role (see the section «Diseases of Genomic Imprinting»).

Child developmental pathology may have a mono- or polygenic nature. Multiple malformations inherited in an autosomal dominant (AD) manner are presented below.

Achondroplasia is a form of dwarfism (due to limb shortening) characterized by macrocephaly and typical radiological features, including shortening of the cranial base, narrowing of the foramen magnum, and shortening and thickening of the tubular bones.

Treacher Collins-Franceschetti syndrome (mandibulofacial dysostosis) is characterized by down-slanting palpebral fissures, coloboma, maxillary and mandibular hypoplasia, partial absence of eyelashes on the lower eyelid, dysplastic ears, sometimes absence of the external auditory canals, deafness, and cleft palate. The inheritance pattern is autosomal dominant with variable expressivity.

Freeman-Sheldon syndrome (whistling face syndrome) is also inherited in an autosomal dominant manner in most cases and is marked by blepharophimosis, strabismus, a long philtrum (increased distance between the Nose and upper lip), a small Mouth with pursed Lips, camptodactyly, and Clubfoot.

Crouzon syndrome is likewise inherited in an autosomal dominant manner; it manifests with hypertelorism, exophthalmos, divergent strabismus, a parrot-beak nose, a short upper lip, maxillary hypoplasia, and mandibular prognathism. Syndactyly, cataracts, papilledema, and optic atrophy are occasionally observed. Visual acuity typically declines in the first years of life and subsequently stabilizes. Cleft palate and Congenital Heart defects are also quite common.

Rubinstein-Taybi syndrome (broad thumb-hallux syndrome) manifests with a symptom complex that includes growth retardation, intellectual disability, broadened terminal Phalanges of the thumbs and halluxes, craniofacial dysmorphisms, a grimace resembling a smile, cryptorchidism, and Malformations of the Brain and Internal Organs.

Various inheritance patterns are possible, including both autosomal recessive (AR) and autosomal dominant (AD) with incomplete penetrance and expressivity (Figs. 8, 10).

Opitz syndrome (types I and II) is characterized by hypertelorism, facial clefts, and ear and heart malformations; in males, it is marked by hypospadias, cryptorchidism, and inguinal hernias.

Poland syndrome is a unilateral defect of the pectoralis major Muscle accompanied by nipple absence, ipsilateral rib defects, and syndactyly.

Polycystic Kidney Disease (adult type) typically manifests after the age of 30. Clinical Features include abdominal pain, bilateral enlargement of the Kidneys, proteinuria, and Hematuria. In 50–60% of patients, arterial Hypertension and progressive renal failure are observed. Occasionally, this condition is diagnosed in children under 10 years of age.

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Fig. 10. Rubinstein-Taybi syndrome (proband 0.2 in the pedigree shown in Fig. 8). Girl K., aged 12:

a — antimongoloid slant of the eyes, hypoplasia of the alae nasi, downturned nasal tip, smiling grimace; b — broad distal phalanges of the fingers; c — broad distal phalanges of the first toes

Van der Woude syndrome is characterized by features such as cleft lip or palate, and pits of the lower lip mucosa.

Aarskog syndrome in males presents with a short stature, round face, hypertelorism, brachydactyly, and shawl Scrotum. Secondary sexual characteristics develop normally. Females exhibit mild or aborted Features of the condition; consequently, an X-linked dominant (XD) mode of inheritance is currently hypothesized for this pathology (heterozygous females).

An XD-inheritance pattern is characteristic of Aicardi syndrome, which is distinguished by unilateral microcephaly, facial Asymmetry, low-set ears, seizures, and specific chorioretinopathy. Pathomorphological examination reveals agenesis of the corpus callosum.

Among multiple congenital anomaly syndromes presumed to be inherited in an autosomal recessive manner, the following should be mentioned.

Bowen syndrome is characterized by craniofacial and skeletal anomalies, congenital glaucoma, heart defects, absence of subcutaneous fat, agenesis of the corpus callosum, and early lethality.

Smith-Lemli-Opitz syndrome manifests as intrauterine growth restriction, microcephaly, ptosis, epicanthus, strabismus, anteverted nares, micrognathia, syndactyly, polydactyly, congenital heart defects, renal and pulmonary anomalies, pyloric stenosis, and intellectual disability. Currently, the etiology of this syndrome is attributed to a mutation in a Gene whose dysfunction impairs Cholesterol METABOLISM (metabolic disorder).

Goldenhar syndrome, characterized by oculo-auriculovertebral Dysplasia, presents at birth with unilateral facial hypoplasia, epibulbar dermoids, coloboma of the upper eyelids, and Anomalies of the auricles and spine.

Jeune syndrome is characterized by asphyxiating thoracic dystrophy, abnormal rib count, growth retardation, limb shortening, renal failure, and congenital heart disease.

Cerebro-oculo-facio-skeletal syndrome is characterized by marked prenatal hypoplasia, microcephaly, microphthalmia, kyphoscoliosis, and joint flexion contractures.

X-linked inheritance is typical of aqueductal stenosis, which is accompanied by Hydrocephalus and corresponding clinical symptoms. Lenz syndrome, which manifests as microphthalmia, digital anomalies, microcephaly, and deformed auricles, is also classified among multiple malformation syndromes of this type. The Inheritance of the syndrome is X-linked recessive; heterozygous females exhibit minimal pathological signs in the form of a narrow face, dental defects, and rudimentary polysyndactyly.

Sporadic cases of multiple malformations belong to pathologies associated with new Mutations, as their inheritance cannot be traced due to high lethality. Such congenital malformations include amniotic band disruption complexes (Adam complex, or congenital amputations) and the VATER association: V (vertebrae) — vertebral defects, A (anal atresia) — imperforate anus, TE (tracheoesophageal) — tracheoesophageal fistulas, and R (radial and renal) — radial dysplasia and renal malformations. Cornelia de Lange syndrome (microcephaly, hypertrichosis, long curled eyelashes, synophrys, long philtrum, anteverted nostrils, psychomotor and physical retardation, and internal organ defects) also occurs sporadically. In some cases, structural rearrangement of chromosome 3 has been described in this syndrome. It is possible that Cornelia de Lange syndrome will also be included in the group of chromosomal abnormalities.

Some AD syndromes occur as sporadic phenomena (new mutations), such as achondroplasia (80% being isolated family cases). This percentage is likely to decrease if the biological father of the affected child is identified in each case.

Polygenic multifactorial inheritance has been described for Poland syndrome (along with AD inheritance in some families); for anencephaly accompanied by adrenal and neurohypophyseal hypoplasia; and for vaginal atresia in women with a normal karyotype (46,XX).

Multiple congenital malformations should be distinguished from anomalads—complexes of malformations that arise as a secondary manifestation of a primary lesion, specifically the primary defect of a certain tissue or organ that triggers The formation of subsequent malformations during embryonic development.

The international congenital anomaly monitoring program currently lacks an indicator for multiple malformations, because modern Research Methods make it possible to diagnose a specific syndrome by identifying the chromosomal or gene defect and the mode of inheritance in each given case.

Hereditary malformations of mutational origin must be differentiated from the consequences of teratogenesis and prolonged modifications, which are neither inherited nor transmitted to subsequent generations.

Congenital malformations of individual organs and systems are part of syndromes or are inherited independently according to one of the specified types: AD, XD, AR, XR, or polygenic. The system of homeobox genes, whose mutations lead to specific disruptions in Embryogenesis, is considered the cause of genetically determined multiple Congenital malformations and defects of individual organs and systems. Currently, this system is being comprehensively studied in order to develop effective diagnostic methods for this pathology.

Treatment of developmental anomalies and defects is surgical and highly effective. Certain defects (such as a diaphragmatic hernia) can be corrected even in the prenatal period. The detection and registration frequency of malformations largely depends on the qualifications of medical personnel and the statistical accounting and reporting forms used. It is precisely the completeness of congenital malformation registration, rather than the genetic EFFECTS OF ENVIRONMENTAL pollution, that explains the differences in their incidence across various countries. For instance, the incidence of such pathology per 1,000 newborns is about 60 in Hungary, 90 in the USA, and, according to our data, has remained close to 50 in Ukraine over a 20-year period with minor annual fluctuations.