Dysmorphic Syndromes



Dysmorphic Syndromes


George E. Tiller



Dysmorphology is the art and science of abnormal physical development. It is often subjective, and distinguishing between familial traits and true dysmorphic features is sometimes difficult. A recognizable pattern of human malformation is dubbed a syndrome. Some syndromes are associated with a single underlying genetic defect or chromosomal anomaly, others have a multifactorial basis (genetic plus environmental), and still others have no apparent genetic basis at all, being simply birth defects. Genetic disorders contribute significantly to morbidity and mortality at all ages. More than 3500 mendelian (single-gene) disorders have been catalogued. It has been estimated that 1% to 2% of newborns have significant birth defects. Although individually rare, genetically related disorders are responsible for one third of all pediatric hospital admissions. We must also appreciate that many genetic disorders are insidious in onset and may present to the clinician in a wide range of age groups.

A three-generation family history is an essential component of the evaluation of a possible genetic disorder. Questions about ethnicity and possible consanguinity are a routine part of this process. The family history is followed by a review of the patient’s medical history and then by a careful, objective physical examination. Anthropometric graphs from appropriate texts can remove some of the subjectiveness involved in determining the disproportionality of body parts. Once a differential diagnosis has been constructed, specific testing can begin, if available. Genetic counseling is the last step in the clinical evaluation, once all the information available has been analyzed.

The objectives of this chapter are to help the reader:



  • Distinguish different mechanisms underlying congenital anomalies


  • Describe the clinical features and molecular basis (if known) of the more common dysmorphic syndromes


CATEGORIES OF CONGENITAL ANOMALIES



  • Malformation: A morphologic defect resulting from an intrinsically abnormal developmental process. Causes may be chromosomal, genetic (a single gene), teratogenic, or idiopathic. Examples are cleft lip, cleft palate, congenital heart defects, and neural tube defects.


  • Deformation: An abnormal form, shape, or position of a body part caused by mechanical forces. The cause is often uterine constraint. Examples are craniosynostosis and clubfoot.


  • Disruption: Destruction of a previously normally forming body part. Causes include amniotic bands and vascular disruption. Examples are limb reduction defects and gastroschisis.


  • Dysplasia: Abnormal organization or proliferation of cells into a tissue. Causes include some single-gene defects. Examples include ectodermal dysplasias and skeletal dysplasias.


  • Sequence: A cascade effect resulting from a single embryologic event that may affect surrounding tissues. Examples include Pierre-Robin sequence, amnion rupture, oligohydramnios, and DiGeorge syndrome.


WHEN TO CONSIDER A DYSMORPHIC SYNDROME

Dysmorphic syndromes must be considered in the presence of:



  • More than one anomaly present


  • Phenotypic variation from parents and siblings


  • Abnormal growth: prenatal (and sometimes postnatal) growth retardation (or overgrowth)


  • Neurologic symptoms (e.g., seizures, mental retardation [MR], abnormal muscle tone, deafness, blindness, speech delay with or without motor delay)



EXAMPLES OF MORE “COMMON” GENETIC SYNDROMES


Achondroplasia



  • Frequency: Most common nonlethal skeletal dysplasia (1 in 26,000)


  • Inheritance: Autosomal dominant (80% new mutations)


  • Features: Short-limbed dwarfism, macrocephaly with frontal bossing and saddle nose, infantile gibbus progressing to lumbar lordosis, trident hand, and tibial bowing (Fig. 42.1)


  • Complications: Infantile hypotonia, apnea secondary to tight foramen magnum, ventriculomegaly, and cervical and lumbar spinal cord compression


  • Primary defect: Fibroblast growth factor receptor 3


Marfan Syndrome



  • Frequency: 1 in 10,000


  • Inheritance: Autosomal dominant (>15% new mutations)


  • Features: Tall, lanky habitus; dolichocephaly and high, arched palate; arachnodactyly, joint laxity; pectus deformity, scoliosis; myopia, ectopia lentis; mitral valve prolapse, aortic root dilatation; dural ectasias (Figs. 42.2, 42.3 and 42.4)


  • Complications: Joint instability, visual impairment, aortic insufficiency, aneurysmal rupture causing sudden death, spontaneous pneumothorax, and pulmonary blebs


  • Treatment: Atenolol or other cardioselective β-blocker; losartan


  • Primary defect: Fibrillin, a connective tissue protein






Figure 42.1 Six-month-old boy with achondroplasia. Note the macrocephaly, frontal bossing, upturned nares, and short limbs.






Figure 42.2 Nine-year-old boy with Marfan syndrome. Note the tall, thin stature.







Figure 42.3 Nine-year-old boy with Marfan syndrome. Note the positive wrist sign.






Figure 42.4 Twelve-year-old boy with Marfan syndrome. Note the positive thumb sign.


Ehlers-Danlos Syndrome



  • Frequency: 1 in 10,000


  • Inheritance: Autosomal dominant (mostly), rarely autosomal recessive


  • Features: Skin hyperelasticity (Fig. 42.5), poor wound healing, excessive bruising; joint laxity (Fig. 42.6), pectus deformity, and scoliosis


  • Complications: Joint instability; aneurysmal rupture causing sudden death (type IV or arterial form only)


  • Primary defects: Type III or V collagen; lysyl hydroxylase; others unknown


  • Remarks: Ten known clinical types of Ehlers-Danlos syndrome, caused by defects in different genes and with varying severity


Osteogenesis Imperfecta



  • Frequency: 1 in 20,000


  • Inheritance: Autosomal dominant, rarely autosomal recessive


  • Features: Vary from mild to lethal (perinatal); osteoporosis, bone fragility causing pathologic fractures (Fig. 42.7); dentinogenesis imperfecta (Fig. 42.8); Wormian bones in occiput; blue sclerae; hearing loss



  • Complications: Pulmonary hypoplasia, death (type II); scoliosis, progressive deformities (type III); short stature (type IV)


  • Primary defect: Type I collagen






Figure 42.5 Eight-year-old boy with Ehlers-Danlos syndrome (type VIII). Note the skin hyperelasticity on the forearm.






Figure 42.6 Eighteen-year-old woman with Ehlers-Danlos syndrome (type II). Note the joint hyperextensibility.


Anhydrotic Ectodermal Dysplasia



  • Frequency: 1 in 10,000


  • Inheritance: X-linked; female carriers mildly affected


  • Features: Hypotrichosis, hypodontia, anhydrosis, heat intolerance, atopy, short stature, and mild MR


  • Primary defect: Ectodysplasin, a transmembrane protein


  • Remarks: Numerous other ectodermal dysplasia disorders are known!






Figure 42.7 Radiograph of term newborn girl with osteogenesis imperfecta. Note the diffuse osteopenia, healed femoral fracture (L), and displaced acute femoral fracture (R).






Figure 42.8 Five-year-old girl with osteogenesis imperfecta. Note the dentinogenesis imperfecta.


Holt-Oram Syndrome (Heart-Hand Syndrome)



  • Frequency: 1 in 100,000


  • Inheritance: Autosomal dominant, variable expression


  • Features: Congenital heart disease (atrial septal defect > ventricular septal defect); finger-like or absent thumb (Fig. 42.9); radial hypoplasia


  • Primary defect: TBX5 gene, a transcription factor


Thanatophoric Dysplasia



  • Frequency: 1 in 50,000 (most common lethal skeletal dysplasia)


  • Inheritance: Sporadic, dominant-acting mutation


  • Features: Short-limbed dwarfism, curved long bones, narrow thorax, and flattened vertebrae (platyspondyly)


  • Complications: Death resulting from pulmonary hypoplasia


  • Primary defect: Fibroblast growth factor receptor 3 (allelic with achondroplasia)


Treacher-Collins Syndrome (Mandibulofacial Dysostosis)

Tags:
Jul 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Dysmorphic Syndromes

Full access? Get Clinical Tree
Get Clinical Tree app for offline access