Chapter 2.

Dysmorphology, Syndromology & Genetics

PRINCIPLES OF DYSMORPHOLOGY

Malformations

Deformations

Comparision of malformations and deformations

Time of onset of malformations and deformations

Disruptions

Interrelationship between malformations, deformations, and disruptions

Minor Anomalies and Their Significance

PRINCIPLES OF SYNDROMOLOGY

Unknown-Genesis Syndromes

Provisionally unique-pattern syndrome

Recurrent-pattern syndromes

Known-Genesis Syndrome

Pedigree syndromes

Chromosomal syndromes

Biochemical defect syndromes

Environmentally induced syndromes

Comments on syndrome delineation process

Sporadic occurance and syndrome delineation

Differences between syndromology and classical medicine

Pace of syndrome delineation

Significance of Syndrome delineation

ANALYSIS OF SELECTED CRANIOFACIAL ANOMALIES

Robin Sequence

Unilateral Craniofacial Microsomia

FORMAL GENETICS

Cytogenetics and Chromosomal Anomalies

Monogenic Inheritance Patterns

Multifactorial Inheritance

Sporadicity

□ Two perspectives on craniosynostosis  (Table 2-1)

① anatomic

② genetic

□ Syndromology의 필요성

① patient care : clinical and laboratory diagnosis, overall diagnosis, patient counseling, risk of recurrence에 대한 연구

② etiology and pathogenesis

ⓐ family history와 genetic study를 통한 etiologic heterogeneity, pathogenetic heterogeneity의 발견

ⓑ syndrom delineation을 통한 질환의 분류와 pathogeneis의 연구에 활용

PRINCIPLES OF DYSMORPHOLOGY

□ Anomalies (building blocks of various syndrome)의 3 types

① malformation : intrinsic abnormal development (embryonic)

② deformation : mechanical (fetal period)

③ disruption : intrinsic normal development

Malformations

1. Def : intrinsically abnormal development에 의한 organ 전부 혹은 일부, body의 larger area의 morphologic defect

2. newborn의 3%가 significant malformation, 1%가 multiple

3. 3 Class      (table 2-2)

① incomplete morphogenesis(mc) : developmental arrest가 가장 흔함

② redundant morphogenesis : redundant str. ⊕ normal counterpart str.

③ aberrant morphogenesis(rare) : no counterpart in normal morphogenesis

4. malformation sequence : known or presumed structural defect로 부터 유도된 multiple defect

: 1o defect가  2o, 3o defect를 trigger → multiple defect

5. malformation은 nonspecific하다. 즉 각 defect가 독립된 한 형태로서  나타날 수도 있으며, 동시에 한 syndrom에 종속적으로 나타날 수도 있다.

ex)	Stickler syndrome(progressive arthroopthalomathy) - Autosomal Dominant

: high myopia, retinal detach, bone & joint anomaly & cleft palate

Rubinstein-Taybi synd. - Broad thumb or normal thumb

Beckwith-Wiedemann - macroglossia & omphalocele

□ 이러한 malformation이 개개의 syndrome에 반드시 나타나는 것은 아니며 syndrome의 진단은 하나의 anomalies에 의해서가 아니라 anomalies의 전반적인 pattern에 의한다.

6. malformation syndrome

① 정의 : primary malformations 이전의 basic defect에 의해 developmentally unrelated malformation sequences가 발생

즉) embryonically noncontiguous area에서 일어난 malformations들이 syndrome을 형성

② true malformation syndrome의 특징 : embryonic pleiotropy

□ malformation sequence : basic defect가 primary malformation level에서 발생

Deformation(신생아의 2%)

1. Def : nondisruptive mechnical force에 의한 신체일부의 abnormal form or position

ex) CDH, cong. postural scoliosis , clubfoot

2. Most important factor : lack of fetal movement

--> late fetal life에 mechanical force에 의한 intrauterine molding에 의해

3. 원인 (table 2-3)

① mechanical (mc)

② malformation (7.6%의 malformation에서 동반된다)

- Spina bifida의 경우 partial leg paralysis로 CDH, clubfoot이 동반 가능하다.

③ functional : cong. hypotonia 등으로 N-M type arthro gryposes 발생가능

# Comparison of malformation & deformation (table 2-4)

# Time of onset of malformation & deformation  (table 2-5)

malformation은 주로 embryonic period에 발생하지만 예외는 있다.

□ position of comfort(Chapple & Davidson)

: deformity를 가진 신생아는 생후 몇 일간 prenatal postures(position of comfort)로 쉽게 folding가능

--> uterus에 의한 fetal movement restraint에 의해 deformity가 유발된다는 것을 보여주는 것

□ deformation sequence(fig. 2-3)

- 정의 : known or presumed mechanical factor 또는 previous structural defect에 의한 multiple deformations

- deformation을 가진 신생아의 1/3에서 2개 이상의 deformities가 관찰

□ malformation의 7.6%에서 이와 연관된 deformation이 관찰

- 이 경우 주로 deformation은 malformation에 의한 2차적 결과로 발생

- central nerveous system and urinary tract malformation

--> fetal movement가 억제 --> deformation 유발

ex) spina bifida(malformation) --> paralysis of leg --> CDH(deformation)

□ Potter sequence (malformation --(induce)--> deformation)

- urinary tract malformation에 의한 amniotic fluid 부족으로 extrinsic force로부터 fetus를 보호하지 못하여 발생

- malformations --( primary oligohydramnios )--> deformation

bilateral renal agenesis,	sirenomelia

severe hypoplastic kidney	deformed face and hand

severe polycystic kidney

urethral atresia

□ Comparison of malformations and deformations(table 2-4)

□ Time of onset of malformations and deformations(table 2-5)

Disruption

1. Def : 정상성장의 breakdown 또는 interference에 의한 morphologic defect

① aberrant tissue band : ring constriction, distal pseudosyndactyly, digit amputaiton

② severe compression in utero : bicornuate uterus, leiomyomas, early amniotic rupture

2. 특징

① sporadic occurrence

② recurrence의 위험은 적다

③ more variable

□ Amniotic rupture sequence에 의한 2가지형의 disruption

① compression-related defects : limb deficiency, body wall deficiency, enrual tube defect

② band- or adhesion-related defect : craniofacial cleft

- single gene에 의해 multiple defect 보임

ex) Trisomy 13 syndrome - holoprosencephaly, VSD, Polydactyly

Minor Anomalies and Their Significance(table 2-7)

PRINCIPLES OF SYNDROMOLOGY

Unknown Genesis Syndrome(60%)

1. provisionally unique-pattern syndrome : 여러개의 anomaly가 보이지만 그것들의 전체적인 pattern을 알수 없는 경우

2. recurrent-pattern syndrome : similar or identical set of anomalies in two of more unrelated pt's

Known genesis syndrome(40%)

1. Pedigree syndrome : Crouzon sydrome

- basic defect는 알수 없으나 가족력을 보이는 경우

2. Chromosomal syndromes : Trisomy 13 syndrome

- cytogenetically defined

3. Biochemical defect syndromes : Hurler syndrome(α-L-iduronidase deficiency)

- sepcific enzymatic disorder(대개 AR)

4. Enviornmentally induced syndrome : fetal alcohol syndrome

Syndrome delineation(fig 2-19)

중요성 : unknown-genesis syndrome delineation과정에서 phenotypic spectrum, natural history, inheritance pattern, risk of recurrence를 파악하게되며 환자의 care나 family counseling에 이들의 정보를 활용

Similarity & difference between syndromology & classical medicine(fig 2-22)

ANALYSIS OF SELECTED CRANIOFACIAL ANOMLIES

□ Etiologic, pathogenetic heterogeneity of craniofacial anomalies(fig 2-23)

Robin sequence :

① micrognathia

② cleft palate

③ glossoptosis

□ AD Stickler's synd. : Ribon sequence가 가장 흔히 관찰되는 syndrome

Unilateral craniofacial microsomia

① deformity 부위 : aural, oral, mandibular growth장애

② 원인 : stapedial a. stem을 형성하는 anastomosis부위에 embryonic hematoma formation (정도에 따라 범위가 결정된다)

□ hematoma의 원인 (heterogenous) : hypoxia, hypertension, pressor drug, salicylate, anticoagulant

③ Other causes

ⓐ recurrent pattern syndrome(Fig 2-28)

ⓑ amniotic band spectrum of disruption

ⓒ intrauterine compression → branchial arch region hematoma유발

□ preauricular tag - accesory auricular hillock ( minimally afected )

: hemifacial microsomia와 한가족에서 자주 발견되나 hematoma에 의해 설명되지는 않음 <-- pathogenetic heterogeneity를 보여줌

Craniosynostosis

1. 3 classic theory

① Virchow(1851) : craniosynostosis가 1o → cranial base deformity가 2o

② Moss(1959) - most popular theory

: cranial base malformation이 1o → cranial suture 조기 유합이 2o

dural attachment가 이러한 aberrant tensile force를 중계한다

③ Park & Powers(1920) : 1o defect in the mesenchymal blastema

→ 2o로 craniosynostosis, cranial base abnormality

2. craniosynostosis 유발 상황 - pathogenetically heterogenous

① human prenatal head constraint : sagittal이 mc, (남>여)

② lack of growth stretch at the suture

ⓐ lack of CNS growth

ⓑ shunted hydrocephaly

ⓒ encephalocele

③ hyperthyroidism, excessive thyroxine treatment

④ Hurler syndrome : sagittal. lambdoid

⑤ various forms of ricket

⑥ hematologic disease : hyperplasia of BM with compensatory overgrowth of bone, thalassemia, SCA, P. vera, congenital hemolytic icterus

⑦ others : ataxia-telangiectasia, epidermal nevus syndrome, job syndrome

□ Apert syndrome

① progressive calcification & fusion

② progressive generalized bony dysplasia & ankylosis of joint

③ progressive limitation of motion

④ progressive overcalsification of cartilaginous portion

FORMAL GENETICS

1. Cytogenetics & chromosomal Anomalies

# cell culture에 사용되는 세포

① small lymphocyte

② fibroblast

③ amniotic fluid cell

④ spontaneous abortion, embryos, fetuses의 viable cell

* Chromosomal study indication (table 2-14)

Miscellaneous indication

① gynecomastia

② preauricular or helical pit(Cat eye syndrome)

③ single umbilical syndrome(tri-18)

④ polydactyly(tri-13)

⑤ ambigouous genitalia

2. Monogenic Inheritance Patterns

① Autosomal dominant trait

② Autosomal recessive trait

③ X-rinked dominant

④ X-rinked Recessive

3. Multifactorial inheritance

* 특징

① relative에서 risk↑

② affected family member가 많을수록 risk↑

③ malformation이 심할수록 relatives의 risk↑

④ 적은 빈도의 sex(M/F)의 relatives가 affect되었을때 risk↑

⑤ 근친상간에서 risk↑

4. Sporadicity