NF-1 is an autosomal dominant disorder of chromosome 17 that occurs in about 1 in 3,000 births. About 50% of affected families have a negative family history; in many of these families, the father is older, suggesting that advanced paternal age may influence the NF-1 mutation. NF-2 is an autosomal dominant disorder of chromosome 22; however, many patients have a negative family history.

Signs and symptoms of NF-1 vary greatly from one family to another and within members of the same family. A patient who initially seems to have mild symptoms may develop more severe problems later.

An infant with this form may present with only café-au-lait spots or may also have congenital glaucoma, plexiform neurofibromas, or pseudoarthrosis. About 90% of patients have Lisch nodules on the iris; as many as 15% develop optic pathway gliomas, which may cause a significant loss of vision.

Cutaneous and other neurofibromas may begin to develop or become more prominent at puberty; pregnancy may exacerbate tumor growth. Some tumors become malignant; about 8% of patients develop neurofibrosarcoma (cancer of the nerve sheath). Other less-specific features may include other types of tumors (such as meningiomas), short stature, seizures, speech and learning disabilities, mental retardation (occasionally), and abnormalities of the cerebral, GI, and renal arteries.

The first sign of NF-2 is usually a central nervous system tumor, such as a spinal or intracranial meningioma, an acoustic neuroma, and occasionally a schwannoma or spinal astrocytoma. Cutaneous neurofibromas may be less conspicuous in this form, and café-au-lait spots may be minimal or even absent. Learning disabilities and other less-specific features characteristic of NF-1 aren’t typically seen in NF-2.

Osteogenesis imperfecta can result from autosomal dominant inheritance of a defect in the amount of Type I collagen, an important part of the bone matrix. Clinical signs may result from defective osteoblastic activity and a defect of mesenchymal collagen (embryonic connective tissue) and its derivatives (sclerae, bones, and ligaments). The reticulum fails to differentiate into mature collagen or causes abnormal collagen development, leading to immature and coarse bone formation. Cortical bone thinning also occurs.

Type I, the most common form of osteogenesis imperfecta, occurs in about 1 in 30,000 live births. Both types I and IV are thought to be inherited as an autosomal dominant trait. Types II and III are believed to be inherited as an autosomal recessive trait.

Clinical severity varies, depending on the type. In type I, fractures characteristically occur from minimal trauma. The sclerae are a deep blue-black color, and the teeth may be yellow or even grayish blue from opalescent dentin. Patients with dental abnormalities are shorter and have more fractures at birth, more frequent fractures, and more severe skeletal deformities than type I patients with normal teeth.

Bowing of the lower limbs is common in this type, as is kyphosis in adults. About 40% of all adults with type I have severely impaired hearing, and virtually all adults have some degree of hearing impairment by age 50. The number of fractures may spontaneously decrease in adolescence.

Type II is characterized by intrauterine fractures due to extreme bone fragility, leading to intrauterine or early infant death. Death usually results from complications of bone fragility, heart failure, pulmonary hypertension, or respiratory failure. Therapeutic intervention doesn’t usually increase survival.

Type III is generally nonlethal. Fractures are usually present at birth and occur frequently in childhood; they typically lead to progressive skeletal deformity and, eventually, impaired mobility. Patients have a poor growth rate; most fall below the third percentile in height for their age. Their sclerae are usually normal or light blue, and their teeth aren’t usually opalescent.

Type IV is characterized by osteoporosis, which leads to increased bone fragility. The sclerae may be light blue at birth but appear normal in adolescents and adults. Bowed limbs may be present at birth, but only 25% of patients have fractures at birth. The number of fractures may decrease spontaneously at puberty, but the majority of patients are short. A few have a skull deformity.

Marfan syndrome is inherited as an autosomal dominant trait of chromosome 15. It’s caused by mutations in the fibrillin-1 gene, producing changes in elastic tissues, especially of the aorta, eye, and skin. Mutations of the fibrillin-1 gene also cause overgrowth of long bones. In 85% of patients with this disease, the family history confirms Marfan syndrome in one parent as well. In the remaining 15%, a negative family history suggests a fresh mutation, possibly from advanced paternal age.

The most common signs and symptoms of this disorder are skeletal abnormalities, particularly excessively long tubular bones and an arm span that exceeds the patient’s height. The patient is usually taller than average for his family (in the 95th percentile for his age), with the upper half of his body shorter than average and the lower half, longer. His fingers are long and slender (arachnodactyly). Weakness of ligaments, tendons, and joint capsules results in joints that are loose, hyperextensible, and habitually dislocated. Excessive growth of the rib bones gives rise to chest deformities such as pectus excavatum (funnel chest).

Eye problems are also common; 75% of patients have crystalline lens displacement (ectopia lentis), the ocular hallmark of Marfan syndrome. Quivering of the iris with eye movement (iridodonesis) typically suggests this disorder. Most patients are severely myopic, many have retinal detachment, and some have glaucoma.

The most serious complications occur in the cardiovascular system and include weakness of the aortic media, which leads to progressive dilation or dissecting aneurysm of the ascending aorta. Such dilation appears first in the coronary sinuses and is commonly preceded by aortic insufficiency. Less-common cardiovascular complications include mitral valve prolapse and endocarditis.

Other associated problems include sparsity of subcutaneous fat, frequent hernias, cystic lung disease, recurrent spontaneous pneumothorax, and scoliosis or kyphosis.

At least 19 different types of collagen have been identified. Collagen is an essential component of connective tissues. The collagen defect in most families with Stickler’s syndrome is caused by a mutation in the type II collagen gene (COL2A1) located on chromosome 12q13. Other families demonstrate linkage to the COL11A2 gene located on chromosome 6p21.3 and others to the COL11A1 gene located on
chromosome 1p21. COL2A1 and COL11A1 are expressed in the hyaline cartilage, vitreous, intervertebral disk, and inner ear. COL11A2 isn’t expressed in the vitreous. Genetic studies have identified a few families who carry the clinical diagnosis of Stickler’s syndrome yet don’t demonstrate linkage to any of the three aforementioned collagen genes, suggesting further genetic heterogeneity (a pattern of traits caused by genetic factors in some cases and nongenetic factors in others).

About 1 in 10,000 people is affected with Stickler’s syndrome. However, this incidence rate is considered conservative because persons with very mild symptoms may never be diagnosed with the syndrome.

The clinical phenotype can consist of ocular, auditory, craniofacial, and skeletal abnormalities. The number of organ systems involved and the specific phenotypic features expressed can vary significantly between affected family members and, in particular, between unrelated affected persons.

Ocular symptoms, particularly high myopia, are common in persons with Stickler’s syndrome, with the exception of those who have COL11A2 mutations. Vitreal abnormalities are considered a hallmark of Stickler’s syndrome, although the abnormalities in the vitreous differ in persons with a COL2A1 mutation from those with a COL11A1 mutation. Retinal detachment resulting in blindness is the most serious ocular complication.

The vitreoretinal degeneration that leads to retinal detachment is much more common in persons with a COL2A1 mutation. Persons with Stickler’s syndrome can also have congenital cataracts and develop glaucoma. Ocular symptoms are typically absent in persons with linkage to COL11A2.

Auditory symptoms include conductive hearing loss secondary to Eustachian tube dysfunction in children with cleft palate or collagen defects in the inner ear apparatus. Sensorineural hearing loss has an earlier onset and tends to be more progressive in persons with a COL11A1 mutation.

Craniofacial features may include micrognathia (small lower jaw) and a flattened midface and nasal bridge. Micrognathia may be associated with some degree of cleft palate (bifid uvula to complete cleft of the palate). Micrognathia associated with glossoptosis places neonates and infants with Stickler’s syndrome at significant risk for episodic obstructive apnea during feeding and when lying flat.

Skeletal symptoms can include joint hypermobility in young children, spondyloepiphyseal dysplasia, and, later, degenerative arthropathy during early adult years. Also related to the collagen defect, scoliosis and mitral valve prolapse can develop in some persons with Stickler’s syndrome.

The gene responsible for cystic fibrosis (located on chromosome 7) encodes a protein that involves chloride transport across epithelial membranes; more than 100 specific mutations of the gene are known. (See Cystic fibrosis transmission risk, page 996.) The immediate causes of symptoms in cystic fibrosis are increased viscosity of bronchial, pancreatic, and other mucous gland secretions and consequent obstruction of glandular ducts. Cystic fibrosis accounts for almost all cases of pancreatic enzyme deficiency in children.

In the United States, the incidence of cystic fibrosis is highest in Whites of northern European ancestry (1 in 2,000 live births) and lowest in Blacks (1 in 17,000 live births), Native Americans, and people of Asian ancestry. The disease occurs equally in both sexes.

The clinical effects of cystic fibrosis may become apparent soon after birth or may take years to develop. They include major aberrations in sweat gland, respiratory, and GI function. Sweat gland dysfunction is the most consistent abnormality. Increased concentrations of sodium and chloride in the sweat lead to hyponatremia and hypochloremia and can eventually induce fatal shock and arrhythmias, especially in hot weather.

Respiratory symptoms reflect obstructive changes in the lungs: wheezy respirations; a dry, nonproductive paroxysmal cough; dyspnea; and tachypnea. These changes stem from thick, tenacious secretions in the bronchioles and alveoli and eventually lead to severe atelectasis and emphysema. Children with cystic fibrosis display a barrel chest, cyanosis, and clubbing of the fingers and toes. They suffer recurring bronchitis and pneumonia as well as associated nasal polyps and sinusitis. Death typically results from pneumonia, emphysema, or atelectasis.

The GI effects of cystic fibrosis occur mainly in the intestines, pancreas, and liver. One early
symptom is meconium ileus; the neonate with cystic fibrosis doesn’t excrete meconium, a dark green mucilaginous material found in the intestine at birth. He develops symptoms of intestinal obstruction, such as abdominal distention, vomiting, constipation, dehydration, and electrolyte imbalance. As the child gets older, obstruction of the pancreatic ducts and resulting deficiency of trypsin, amylase, and lipase prevent the conversion and absorption of fat and protein in the GI tract. The undigested food is then excreted in frequent, bulky, foul-smelling, pale stools with a high fat content. This malabsorption induces poor weight gain, poor growth, ravenous appetite, distended abdomen, thin extremities, and sallow skin with poor turgor. The inability to absorb fats results in a deficiency of fat-soluble vitamins (A, D, E, and K), leading to clotting problems, retarded bone growth, and delayed sexual development. Males may experience azoospermia and sterility; females may experience secondary amenorrhea but can reproduce. A common complication in infants and children is rectal prolapse secondary to malnutrition and wasting of perirectal supporting tissues.

In the pancreas, fibrotic tissue, multiple cysts, thick mucus, and eventually fat replace the acini (small, saclike cluster of cells normally found in this gland), producing symptoms of pancreatic insufficiency: altered pancreatic enzymes and insufficient insulin production, abnormal glucose tolerance, and glycosuria. About 15% of patients have adequate pancreatic exocrine function for normal digestion and, therefore, have a better prognosis. Biliary obstruction and fibrosis may prolong neonatal jaundice. In some patients, cirrhosis and portal hypertension may lead to esophageal varices, episodes of hematemesis and, occasionally, hepatomegaly.