AUTOSOMAL DOMINANT DISORDERS
Neurofibromatosis, Marfan syndrome, achondroplasia, osteogenesis imperfecta, and the craniosynostoses are among the most well-known autosomal dominant disorders. There are many other common autosomal dominant disorders, including Treacher Collins syndrome, associated with a distinct craniofacial phenotype including malar and mandibular hypoplasia, and Noonan syndrome, which has a phenotype similar to Turner syndrome and is characterized by short stature and a webbed neck. Two other common genetic disorders whose causative genes were recently identified and found to be dominant mutations are CHARGE syndrome and Cornelia de Lange syndrome.
1. Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF-1) is one of the most common autosomal dominant disorders, occurring in 1 per 3000 births and seen in all races and ethnic groups. In general, the disorder is progressive, with new manifestations appearing over time. Neurofibromatosis type 2 (NF-2), characterized by bilateral acoustic neuromas, with minimal or no skin manifestations, is a different disease caused by a different gene.
The gene for NF-1 is on the long arm of chromosome 17 and seems to code for a protein similar to a tumor suppresser factor. NF results from many different mutations of this gene. Approximately half of all NF cases are caused by new mutations. Careful evaluation of the parents is necessary to provide accurate genetic counseling. Recent evidence suggests that penetrance is close to 100% in those who carry a gene variant if individuals are examined carefully.
Café au lait (hyperpigmented), light brown macules may be present at birth, and the majority of individuals with NF-1 will have more than six by age 1 year. Neurocutaneous findings are declarative by age 8 years. Neurofibromas are benign tumors consisting of Schwann cells, nerve fibers, and fibroblasts; they may be discrete or plexiform. The incidence of Lisch nodules, which can be seen with a slit lamp, also increases with age. Affected individuals commonly have a large head, bony abnormalities on radiographic studies, scoliosis, and a wide spectrum of developmental problems. Half of NF-1 patients will experience some form of intellectual delay. (For more details of medical evaluation and treatment, see Chapter 25 of this book.) Useful information is provided on the following website: http://www.nfinc.org.
Hyperpigmented macules can occur in other conditions such as McCune-Albright, Noonan, Leopard, and Banayan-Riley-Ruvalcaba (BRR) syndromes. The genes for NF-1, Noonan, and Leopard syndromes are molecules which control cell cycling through the RAS-MAPK signal transduction pathways; therefore, it is not surprising that some features can be shared.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Skeletal abnormalities (Ghent criteria).
Dilation of the aortic root.
Positive family history in some cases
Genetic testing is available for mutations causing Marfan syndrome, but the diagnosis remains largely clinical and is based on the Ghent criteria (available at: http://www.genereviews.org). Children can present with a positive family history, suspicious skeletal findings, or ophthalmologic complications. Motor milestones are frequently delayed due to joint laxity. Adolescents are prone to spontaneous pneumothorax. Dysrhythmias may be present. Aortic and valvular complications are not common in children but are more likely in sporadic cases. The characteristic facies is long and thin, with down-slanting palpebral fissures, malar flattening, and retrognathia. The palate is high arched, and dentition is often crowded. Mutations in the gene for fibrillin-1 (FBN1), an extracellular matrix protein (ECM), are causative.
Homocystinuria should be excluded through metabolic testing in all individuals with marfanoid skeletal features. An X-linked recessive disorder, Lujan syndrome, combines marfanoid habitus with cognitive disability. Other connective tissue disorders, Ehlers-Danlos syndrome, and Stickler syndrome should also be considered.
Mutations in the gene for fibrillin-2 (FBN2) and in transforming growth factor β (TGFβ) pathway can also produce phenotypes that fit in the criteria for clinical diagnosis of Marfan syndrome. Beals syndrome (FBN2), Shprintzen-Goldberg syndrome (SKI1), aneurysm-osteoarthritis syndrome, syndromic thoracic aortic aneurysms, and Loeys-Dietz syndromes (TGFβ pathway) are distinct connective tissue disorders with different medical management and prognostic implications. The reader is referred to reviews available at http://www.genereviews.org for descriptions of these disorders.
The skeletal problems including scoliosis are progressive. Astigmatism and myopia are very common and surveillance for lens dislocation is necessary.
The most serious associated medical problems involve the heart. Although many patients with Marfan syndrome have mitral valve prolapse, the most serious concern is progressive aortic root dilation, which may lead to aneurysmal rupture and death, and progressive or acute valvular (aortic more frequently than mitral) incompetency.
Families and practitioners seeking additional information about Marfan syndrome can be referred to the National Marfan Foundation (http://www.marfan.org).
Medical treatment for patients with Marfan syndrome includes surveillance for and appropriate management of the ophthalmologic, orthopedic, and cardiac issues. Serial echocardiograms are indicated to diagnose and follow the degree of aortic root enlargement, which can be managed medically or surgically, in more severe cases. Prophylactic β-adrenergic blockade or angiotensin II receptor antagonists can slow the rate of aortic dilation and reduce the development of aortic complications.
Genetic testing for mutations in genes associated with aortopathy in patients with arterial dilatation should be considered in all individuals with Marfan syndrome as penetrance is variable and apparently unaffected family members can carry and pass on mutations.
Achondroplasia, the most common form of skeletal dysplasia, is caused by a mutation in FGFR3.
The classic phenotype includes relative macrocephaly, mid-face hypoplasia, short-limbed dwarfism, and trident-shaped hands. The phenotype is apparent at birth. Individuals with achondroplasia are cognitively normal.
Orthopedic intervention is necessary for spinal problems including severe lumbar lordosis and gibbus deformity. Long bone lengthening surgery may help to improve upper extremity function.
Head circumference during infancy must be closely monitored and plotted on a diagnosis-specific head circumference chart. Bony overgrowth at the level of the foramen magnum may lead to progressive hydrocephalus and brainstem compression, and may warrant neurosurgical intervention.
Many patients find support through organizations such as the Little People of America, at the following website: http://www.lpaonline.org.
The vast majority of cases (approximately 90%) represent a new mutation. Two heterozygous parents with achondroplasia have a 25% risk of having a child homozygous for FGFR3 mutations, which is a lethal disorder.
4. Osteogenesis Imperfecta
Osteogenesis imperfecta (OI), or brittle bone disease, is a relatively common disorder. More than 85% of cases are caused by dominant mutations affecting COL1A1 and COL1A2. Rarer forms of OI are caused by mutations in other genes and may be inherited as autosomal.
The four most common forms of OI are:
Type I, a mild form, with bony fractures after birth and blue sclerae.
Type II, usually lethal in the newborn period with multiple congenital fractures and severe lung disease.
Type III, a severe form causing significant bony deformity secondary to multiple fractures (which are both congenital and after birth), blue sclerae, short stature, and mild restrictive lung disease.
Type IV, another mild form with increased incidence of fracturing after birth; dentinogenesis imperfecta is common.
Geneticists and Endocrinologists are now treating OI patients with different forms of bisphosphonate compounds, which can reduce incidence of fracture and improve bone density. Patients should also be followed by an experienced orthopedist, as rodding of long bones and surgery to correct scoliosis are often required. Hearing assessments are indicated, because of the association between OI and deafness, as is close follow-up for dentinogenesis imperfecta.
DNA analysis in blood can confirm mutations in COL1 which cause OI. The milder forms are often inherited as a dominant trait, while the more severe forms of OI generally result from new mutations.
5. Craniosynostosis Syndromes
The craniosynostosis disorders are common dominant disorders associated with premature fusion of cranial sutures. This class of disorders is usually caused by mutations in FGFR genes.
Crouzon syndrome is the most common of these disorders and is associated with multiple suture fusions, but with normal limbs. Other craniosynostosis disorders have limb as well as craniofacial anomalies, and include Pfeiffer, Apert, Jackson-Weiss, and Saethre-Chotzen syndromes.
Patients with craniosynostosis often have shallow orbits, midface narrowing that may result in upper airway obstruction, and hydrocephalus that may require shunting. Children with craniosynostosis may require multiple-staged craniofacial and neurosurgical procedures to address these issues, but usually have normal intelligence.
CHARGE syndrome is a common genetic disorder presenting with unusual features, birth defects, intellectual disabilities, and abnormalities in vision and hearing. The acronym CHARGE serves as a mnemonic for associated abnormalities that include Colobomas, congenital Heart disease, choanal Atresia, growth Retardation, Genital abnormalities (hypogenitalism), and Ear abnormalities, with deafness. Facial asymmetry is a common finding. CHARGE is caused by mutations in the CHD7 gene on chromosome 8q. A website with information on CHARGE syndrome is available at http://www.chargesyndrome.org/.
et al: CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin Genet 2012 81:234–239
7. Cornelia de Lange Syndrome
Cornelia de Lange syndrome is characterized by severe growth retardation; limb, especially hand, reduction defects (50%); congenital heart disease (25%); and stereotypical facies with hirsutism, medial fusion of eyebrows (synophrys), and thin, down-turned lips. The course and severity are variable, and milder presentations may be inherited as a dominant trait.
Heterozygous mutations in the cohesin regulator, NIPBL, or the cohesin structural components SMC1A and SMC3, have been identified in approximately 65% of individuals with CdLS. Cohesin regulates sister chromatid cohesion during mitosis and meiosis. In addition, cohesin has been demonstrated to play a critical role in the regulation of gene expression. Furthermore, multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-stranded DNA break repair, chromatin remodeling, and maintaining genomic stability.
KL: Recognizable Patterns of Human Malformation, 6th ed. Philadelphia, PA: Elsevier; 2013.
et al: High Rate of Mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet 2013;50:299–344
Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease, and mildly dysmoprhic features. Feeding problems may result in failure to thrive. Mild developmental delays are often present, but intelligence may be normal. Noonan syndrome and Noonan-like disorders are caused by mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway, and thus are often called as “RASopathies.” Noonan syndrome is the most common of these disorders, usually caused by mutations in PTPN11. Other related disorders include Cardiofacial Cutaneous syndrome and Costello syndromes. A DNA panel that screens for more than 12 genes in this pathway can help confirm a diagnosis. Because mutations in NF-1 causing neurofibromatosis also affect RAS proto-oncogene signaling, it is not surprising that there is an NF-1 subtype with an associated Noonan phenotype.
AUTOSOMAL RECESSIVE DISORDERS
The gene for cystic fibrosis, CFTR, is found on the long arm of chromosome 7. Approximately 1 in 22 persons are carriers. Many different mutations have been identified; the most common mutation in the Caucasian population is known as Δ F508.
(For more details on medical management of cystic fibrosis, see Chapters 19 and 22.)
2. Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz syndrome is a metabolic disorder in the final step of cholesterol production, resulting in low cholesterol levels and accumulation of the precursor 7-dehydrocholesterol (7-DHC). Because cholesterol is a necessary precursor for sterol hormones, and CNS myelin, and cholesterol content is crucial for the integrity of all cell membranes, the medical consequences of both cholesterol deficiency and 7-DHC accumulation are complex and severe. Also, 7-DHC is oxidized into substances called oxysterols, which are toxic to the retinal and brain.
Patients with Smith-Lemli-Opitz syndrome present with a characteristic phenotype, including dysmorphic facial features (Figure 37–8), multiple congenital anomalies, hypotonia, growth failure, and intellectual disability. Mild cases may present with autism and 2-3 toe syndactyly. The diagnosis can be confirmed via a blood test looking for the presence of the precursor, 7-DHC. DNA analysis of mutations in the DHR7 gene is also available, as is prenatal testing.
Child with Smith-Lemli-Opitz syndrome, featuring bitemporal narrowing, upturned nares, ptosis, and small chin.
Treatment with cholesterol can ameliorate the growth failure and lead to improvement in medical issues, although treatment does not cure this complex disorder. Antioxidant treatment is being used to prevent progressive retinal degeneration caused by oxysterol accumulation.
3. Sensorineural Hearing Loss
Although there is marked genetic heterogeneity in causes of sensorineural hearing loss, including dominant, recessive, and X-linked patterns, nonsyndromic, recessively inherited deafness is the predominant form of severe inherited childhood deafness. Several hundred genes are known to cause hereditary hearing loss and deafness. The hearing loss may be conductive, sensorineural, or a combination of both; syndromic or nonsyndromic; and prelingual (before language develops) or postlingual (after language develops). The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination; family history; ancillary testing (such as CT examination of the temporal bone); and molecular genetic testing. Panels screening for more than 100 genetic forms of hearing loss are available for many types of syndromic and nonsyndromic deafness.
Edi Lúcia Sartorato, Karen Friderici, Ignacio Del Castillo: Genetics of deafness. Genet Res Int 2012;2012: (Article ID 562848). doi:10.1155/2012/562848
4. Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder in which anterior horn cells in the spinal cord degenerate. The mechanism for the loss of cells appears to involve apoptosis of neurons in the absence of the product of the SMN1 (survival motor neuron) gene located on chromosome 5q. Loss of anterior horn cells leads to progressive atrophy of skeletal muscle. The disorder has an incidence of approximately 1 in 12,000, with the majority of the cases presenting in infancy. Carrier frequencies approach 1 in 40 in populations with European ancestry.
Three clinical subtypes are recognized based on age of onset and rate of progression. SMA I is the most devastating. Mild weakness may be present at birth but is clearly evident by 3 months and is accompanied by loss of reflexes and fasciculations in affected muscles. Progression of the disorder leads to eventual respiratory failure, usually by age 1 year. Symptoms of SMA II begin later, with weakness and decreased reflexes generally apparent by age 2 years. Children affected with SMA III begin to become weak as they approach adolescence.
Homozygous deletion of exon 7 of SMN1 is detectable in approximately 95%–98% of cases of all types of SMA and confirms the diagnosis. The SMN1 region on chromosome 5q is complex and variability in presentation of the disorder involves expression of up to three copies of the neighboring SMN2 gene. More severe phenotypes have fewer SMN2 copies. Approximately 2%–5% of patients affected with SMA will be compound heterozygotes in whom there is one copy of SMN1 with exon 7 deleted and a second copy with a point mutation.
Prenatal diagnosis is available through genetic testing, but careful molecular analysis of the proband and demonstration of carrier status in parents is advised since, in addition to the problem of potential compound heterozygosity, 2% of cases occur as a result of a de novo mutation in one SMN1 allele. In this case, one of the parents is not a carrier and recurrence risks are low. Carrier testing is further complicated by a duplication of SMN1 in 4% of the population that results in there being two SMN1 genes on one of their chromosomes. Hence, reproductive risk assessment, carrier testing, and prenatal diagnosis of SMA are best undertaken in the context of careful genetic counseling.
1. Duchenne & Becker Muscular Dystrophies
Duchenne muscular dystrophy (DMD) results from failure of synthesis of the muscle cytoskeletal protein dystrophin. The gene is located on the X chromosome, at position Xp12. Approximately 1 in 4000 male children is affected. Mutations in the same gene that result in partial expression of the dystrophin protein produce a less severe phenotype, Becker muscular dystrophy (BMD). In both DMD and BMD, progressive degeneration of skeletal and cardiac muscle occurs. Boys with DMD exhibit proximal muscle weakness and pseudohypertrophy of calf muscles by age 5–6 years. Patients become nonambulatory by their early teens. Serum creatine kinase levels are markedly elevated. Boys with DMD frequently die in their twenties of respiratory failure and cardiac dysfunction. The prognosis for BMD is more variable. Although corticosteroids are useful in maintaining strength, they do not slow progression of the disorder. Evolution of the natural history of dystrophinopathies in females is demonstrating an increased incidence of serious cardiovascular disease, including cardiomyopathy and arrhythmias.
The gene for dystrophin is very large and a common target for mutation. Large deletions or duplications can be detected in the gene for dystrophin in 65% of cases. Molecular analysis has largely replaced muscle biopsy for diagnostic purposes.
One-third of DMD cases presenting with a negative family history are likely to be new mutations. Genetic counseling is complicated by the fact that germline mosaicism for mutations in the dystrophin gene occur in approximately 15%–20% of families, which is among the highest rates for this otherwise rare phenomenon. It is also necessary to look for mutations in all sisters of affected boys. Since mutations are now detected in the great majority of DMD cases, there is considerably less need for estimating carrier risks based on creatine kinase levels or using genetic linkage for prenatal diagnosis. Nonetheless, counseling and prenatal diagnosis remain difficult in some families. (Additional information about muscular dystrophies is included in Chapter 25.)
Hemophilia A is an X-linked, recessive, bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. (See Chapter 30 for additional discussion.)