Genetic Disorders Dr Essam AL AGEELI Assistant professor of Medical Genetics DES of Medical Genetics, Paris-France.

Objectives To define the types of congenital anomalies which may occur

and their underlying causes.

To discuss an approach to the diagnosis of the neonate with

congenital anomalies.

To be familiar with the genetic basis of selective syndromes.

To known the common features of selective syndromes.

Clinical approach to congenital malformation Dysmorphology: Recognition and study of birth defects and

syndromes. David Smith 1960

Terminology: o Syndrome o Malformation o Deformation o Disruption o Sequence o Association o Dysplasia

Syndrome: A set of developmental anomalies occurring together, result of a single etiology.

Malformation: primary intrinsic anomalies of development, usually occur before 10 weeks of development.

Deformation: Anomaly due to extrinsic mechanical cause

Disruption: destruction of normally programmed structures. e.g limb defect by amniotic band

Sequence: A pattern of developmental anomalies due to isolated anomaly.

Association: Recognized pattern of malformations in which the initiating cause is unknown and the anomalies are not the result of a sequence. e.g VACTERL

(Vertebral defect, Anal atresia, Cardiac anomalies, Tracheo-oesophageal fistula, oEsophageal

atresia, Renal anomalies and Limb defects)

Dysplasia: Structural changes due to abnormal cellular organization within a tissue.

Approach to a child with Genetic disorder

History: - Family (draw the family tree)

- Pregnancy (Bleeding, fever, teratogenic exposure, IUGR, oligo/polyhydramnios, GDM, HTN)

- Neonatal (Including birth history and growth parameter)

- Developmental milestones - Behavior - Vision, hearing, seizures

Physical Examination (including photograph) Further investigation (  Bio,  Karyotype,  FISH,….)

Common Genetic Disorders Chromosomal abnormality syndromes

Down syndrome Turner syndrome Klinefelter syndrome

Microdeletion syndromes

DiGeorge syndrome Angelman/Prader-Willi syndromes Williams syndrome

Mutational syndromes

CHARGE syndrome Neurofibromatosis 1 (NF1) Noonan syndrome

Chromosomal abnormality syndromes

Down syndrome Turner syndrome

Down syndrome (T21) 1 in 700 live births. Risk increase with Maternal age (> 37 = risk 1/250) >60% spontaneously aborted 20% stillborn Clinical features: Distinct facial features Sever Hypotonia (Lead to poor feeding) Hyper-laxity of joints Developmental delays Mental Retardation (IQ usually <50) Congenital heart malformations (40%) Many other associated features

Head and neck Brachycephaly Upper-slanting palpebral fissures Epicanthal folds Flat nasal bridge Small low set ears or dysplastic

ears Open mouth Protruding tongue Short neck Excessive skin at the nape of neck

Extremities Short broad hands Short fifth finger Incurved fifth finger

(clinodactyly) Transverse palmer crease Space between first and

second toe Hyper-laxity of joints

Clinical findings

Most common problems in DS Congenital heart defect

Atrioventricular septal defect (AVSD), VSD, ASD, PDA, mitral valve prolapse, AR and MR Gastrointestinal conditions

Gastroesophageal reflux, constipation, Duodenal atresia, Esophageal atresia, Hirschsprung’s disease, celiac disease.

Growth Short stature, obesity.

ENT problems Frequent Otitis Media, sinusitis, hearing loss and obstructive sleep apnea

Ophthalmological problems Congenital cataract, refractory error, strabismus, nystagmus

Endocrine problems Hypothyroidism, hyperthyroidism, DM1

Orthopedic complication Risk of spinal injury due to excessive mobility of atlas (C1) and the axis (C2)

1.5 % have risk of leukemia (AML, ALL)

Trisomy 21: 47,XX,+21

three separate copies of chromosome 21

The different mechanisms of chromosomes can cause Down syndrome

1. 95% result of Non-disjunction during cell division.

Non-disjunction

Non-disjunction

3. 2% have mosaicism with normal and trisomy 21 cell lines

4. 1% result from different chromosomal rearrangement.

2. 2% due to Robertsonian translocation

Turner syndrome

Turner syndrome Complete or partial absence of

2nd X chromosome in female. In 1/2500 of live-born girls 10% of spontaneous abortion Caused by Non-disjunction.

Clinical features

The phenotype is highly variable In Neonate

Lymphoedema Webbed neck Low posterior hairline Prominent low set ears rotated posteriorly High arched palate Wide space nipple

In Adulthood Short stature (due to gene SHOX) Premature ovarian failure Absent of secondary sexual characteristic (menses and breast development) Arm rotated out slightly at elbow joints

Other associated conditions

Most of girls with TS have normal IQ Cardiovascular defect:

Bicuspid aortic valve, dilated ascending aorta , aortic coarctation

Hypertension (HTN) Frequent Otitis Media and hearing loss Scoliosis, shortened of IV metacarpal bone Drooping eyelids (ptosis) Horseshoe Kidney Hypothyroidism

Microdeletion syndromes

DiGeorge syndrome Angelman/Prader-Willi syndromes Williams syndrome

DiGeorge syndrome

DiGeorge syndrome

Velocardiofacial syndrome, CATCH 22, Microdeletion 22q11.2 1st microdeletion syndrome 1/4000 live birth Deletion of 22q11.2 region including TBX1 gene

Phenotypes Phenotype very variable. Cardinal signs (CATCH) • C ardiac defect (VSD, right aortic arch,TOF) • A bnormal face • T hymus hypoplasia (deficit of immunity- recurrent infections) • C left palate (Poor feeding, Nasal speech) • H ypocalcemia ( hypo-parathyroidism)

Other associated conditions: Developmental delay (milestones, speech) Learning difficulties (spec. in Math.) Renal Malformations (hypoplasia, agenesis) Hearing loss Anomalies of extremities (polydactyly) Scoliosis

• Narrow palpebral fissure

• Hypertolerism • Wide nasal

bridge • Small mouth • Small low set

ears

Angelmam/Prader-Willi syndrome

Angelman / Prader-Willi Syndromes

Deletion in 15q11-q13 region in maternal chromosome 15

Characterized by : Intellectual and

developmental delay Absence of speech, Seizures Jerky movements Spontaneous burst of

laughter or smiling Specific pattern of EEG Facial features: maxillary

hypoplasia, deep set eyes, large mouth with protruded tongue, prognathia and microcephaly.

Deletion in 15q11-q13 region in paternal chromosome 15

Characterized by: Neonatal hypotonia Failure to thrive Developmental delay, mild mental

retardation Early onset obesity related to

behavioral problem of excessive eating

Short stature Hypogonadism and pubertal

insufficiency Facial features: almond shaped,

upper slanted palpebral fissures, narrow bifrontal diameter, strabismus and thin upper lip.

AS incidence is 1/12.000 to 1/20.000 PWS incidence is 1/10.000 to 1/30.000

The possible causes of AS/PWS

• Etiology Angelman Prader-Willi

• Localisation 15q11-q13 15q11-q13

• Genes missing maternels paternels

1. Microdeletion 70 % 70 % 2. Uniparental disomy paternal 5% - 3. Uniparental disomy maternal - 25% 4. Mutation of UBE3A gene 20% - 5. Imprinting defect 5% 5%

Syndrome of PWS/AS

Deletion 15q12.1)

Normal chromosome 15

Fluorescent in situ hybridization (FISH)

Williams syndrome

Williams syndrome

1/8.000- 1/20.000 births Due to microdeletion of 7q11.23 region (ELN gene)

Characterized by :

Deficit intellectual Distinct dysmorphic features Cardiovascular +/- renal malformations Neonatal hypercalcemia Characteristic Behavior (hyper-social personality)

o Coarse face o Broad forehead o Periorbital oedema o Medial eyebrow flare o Small upturned nose o Long philtrum o Wide mouth with

inverted lower lip o Full cheeks o Small chin

Most associated clinical features Poor feeding, constipation, vomiting (leading to FFT) Inguinal hernia in 1/3 of cases Irritability (crying frequently) Developmental delay with learning difficulties Idiopathic hypercalcemia (disappear spontaneously in18-24

months) Supravalvular aortic stenosis, peripheral pulmonary artery

stenosis, pulmonary valve stenosis, VSD, ASD and renal artery stenosis

Hyperacousis ( sensitive to noise) Nephrocalcinosis Joint laxity Dental abnormality

Mutational syndromes CHARGE syndrome Neurofibromatosis

CHARGE syndrome

CHARGE syndrome C : Coloboma of the eye H : Heart defects A : Atresia of the choanae R : Retardation of growth and/or development G : Genitourinary anomalies E : Ear anomalies and/ or Deafness Cranial nerve dysfunction have been added to criteria. Diagnostic criteria required 4 of 6 of CHARGE

features

1/10000 live births Mutation in CHD7 gene on 8q12.1 Most common facial features : square face, broad

nasal bridge, abnormal ear

Diagnostic Criteria Major criteria Minor criteria Diagnostic criteria

Coloboma (iris, retina,..) Facial palsy CHARGE typical 3 Majors

or 2 Majors 2 Minors

Choanal atresia External ear anomalies

Cranial nerve dysfunction (Bulb olfactif anomaly)

Heart defects

Ear anomalies (semi-circular canal hypoplasia)

Genital hypoplaisa CHARGE partial 2 Majors 1 Minor

Tracheo-esophageal fistula or atresia

Renal anomalies CHARGE atypical 2 Majors

or 1 Major 2 Minors

Cleft palate or lip

Short stature

Deficit intellectual

Neurofibromatosis syndrome

NF1 1/3000 live births NF1 caused by mutation in neurfibromine (NF1) gene on 17q11.2 Clinical manifestation extremely variable.

Diagnostic criteria

Required at least 2 or more of the features listed below:

1. ≥  6 café au lait macules larger than 5 mm in prepubertal individuals and larger than 15 mm in postpubertal individuals

2. ≥  2 neurofibromas of any type or 1 plexiform neurofibroma 3. Freckling in the axillary or inguinal regions 4. Optic glioma 5. ≥  2 Lisch nodules (iris hamartomas) 6. Bone abnormalities (sphenoid bone dysplasia, bowed leg,

pseudoarthrosis and scoliosis) 7. A first-degree relative with NF-1 according to the above criteria

Neurofibroma

Café au lait macula

Axillary freckling Plexiform Neurofibroma

Lisch nodules

Other associated clinical features

Tumors Plexiform neurofibromas (25%) Malignant peripheral nerve sheath tumors (5-10%) CNS glioma (2%) Acoustic neuroma Phaeochromocytoma, rhabdomyosarcoma, neuroblastoma (rare)

Mental retardation (Mild to severe)

Short stature Epilepsy Hypertension (due to renal artery stenosis, Phaeochromocytoma)

References

Book • SMITH’S

Recognizable Patterns of Human Malformation

Websites • http://www.genetests.org/by-genereview/ • http://www.orpha.net/consor/cgi-bin/Disease.php?lng=EN